hit – heparin induced thrombocytopenia: new …hit – heparin induced thrombocytopenia: new...
TRANSCRIPT
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
The Paradox
Heparin
Thrombocytopenia
Heparin + Thrombocytopenia
Thrombosis
Bleeding
Bleeding
HIT
bull Is it important
An extreme prothrombotic diathesis
bull Venous or arterial thromboemboli
bull Without prompt and effective treatment the likely outcome is ndash Death in 20 to 30 ndash Limb amputation in 10 to 20 ndash Residual deficits in survivors related to strokes
myocardial infarctions and pulmonary emboli
bull Ptrsquos without a thrombus on presentation (isolated HIT) have a risk of 50 for developing one
bull Is it prevalent
For patients receiving porcine UFH in therapeutic doses either by IV or subcutaneous (SC) for the treatment of venous or arterial thrombosis the risk of HIT has been estimated at approximately
1
Warkentin TE Greinacher A eds Heparin-induced thrombocytopenia 3rd ed 2004107-148 Marcel Dekker New York NY
bull What is HIT ndash Definitin ndash Subtypes ndash Pathophysiology ndash Clinical picture
bull When to suspect bull How to diagnose bull What to do
ndash Immediate management bull Before diagnosis bull After diagnosis
ndash Long term management bull Can heparin be used again bull Preventable disorder
Heparin Induced Thrombocytopenia
bull HIT
(heparin-induced thrombocytopenia) bull HAT
(heparin-associated thrombocytopenia)
HAT Syndrome
Non-immune heparin associated thrombocytopenia (HIT Type I)
bull Associated with an early (within 4 days) and usually mild decrease in platelet count (rarely lt100 x 109L)
bull Typically recovers within 3 days despite continued use of heparin
bull Nonimmunologic mechanisms (mild direct platelet activation by heparin)
bull Not associated with any major clinical sequelae bull Occurs primarily with high dose iv heparin
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
The Paradox
Heparin
Thrombocytopenia
Heparin + Thrombocytopenia
Thrombosis
Bleeding
Bleeding
HIT
bull Is it important
An extreme prothrombotic diathesis
bull Venous or arterial thromboemboli
bull Without prompt and effective treatment the likely outcome is ndash Death in 20 to 30 ndash Limb amputation in 10 to 20 ndash Residual deficits in survivors related to strokes
myocardial infarctions and pulmonary emboli
bull Ptrsquos without a thrombus on presentation (isolated HIT) have a risk of 50 for developing one
bull Is it prevalent
For patients receiving porcine UFH in therapeutic doses either by IV or subcutaneous (SC) for the treatment of venous or arterial thrombosis the risk of HIT has been estimated at approximately
1
Warkentin TE Greinacher A eds Heparin-induced thrombocytopenia 3rd ed 2004107-148 Marcel Dekker New York NY
bull What is HIT ndash Definitin ndash Subtypes ndash Pathophysiology ndash Clinical picture
bull When to suspect bull How to diagnose bull What to do
ndash Immediate management bull Before diagnosis bull After diagnosis
ndash Long term management bull Can heparin be used again bull Preventable disorder
Heparin Induced Thrombocytopenia
bull HIT
(heparin-induced thrombocytopenia) bull HAT
(heparin-associated thrombocytopenia)
HAT Syndrome
Non-immune heparin associated thrombocytopenia (HIT Type I)
bull Associated with an early (within 4 days) and usually mild decrease in platelet count (rarely lt100 x 109L)
bull Typically recovers within 3 days despite continued use of heparin
bull Nonimmunologic mechanisms (mild direct platelet activation by heparin)
bull Not associated with any major clinical sequelae bull Occurs primarily with high dose iv heparin
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
bull Is it important
An extreme prothrombotic diathesis
bull Venous or arterial thromboemboli
bull Without prompt and effective treatment the likely outcome is ndash Death in 20 to 30 ndash Limb amputation in 10 to 20 ndash Residual deficits in survivors related to strokes
myocardial infarctions and pulmonary emboli
bull Ptrsquos without a thrombus on presentation (isolated HIT) have a risk of 50 for developing one
bull Is it prevalent
For patients receiving porcine UFH in therapeutic doses either by IV or subcutaneous (SC) for the treatment of venous or arterial thrombosis the risk of HIT has been estimated at approximately
1
Warkentin TE Greinacher A eds Heparin-induced thrombocytopenia 3rd ed 2004107-148 Marcel Dekker New York NY
bull What is HIT ndash Definitin ndash Subtypes ndash Pathophysiology ndash Clinical picture
bull When to suspect bull How to diagnose bull What to do
ndash Immediate management bull Before diagnosis bull After diagnosis
ndash Long term management bull Can heparin be used again bull Preventable disorder
Heparin Induced Thrombocytopenia
bull HIT
(heparin-induced thrombocytopenia) bull HAT
(heparin-associated thrombocytopenia)
HAT Syndrome
Non-immune heparin associated thrombocytopenia (HIT Type I)
bull Associated with an early (within 4 days) and usually mild decrease in platelet count (rarely lt100 x 109L)
bull Typically recovers within 3 days despite continued use of heparin
bull Nonimmunologic mechanisms (mild direct platelet activation by heparin)
bull Not associated with any major clinical sequelae bull Occurs primarily with high dose iv heparin
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
An extreme prothrombotic diathesis
bull Venous or arterial thromboemboli
bull Without prompt and effective treatment the likely outcome is ndash Death in 20 to 30 ndash Limb amputation in 10 to 20 ndash Residual deficits in survivors related to strokes
myocardial infarctions and pulmonary emboli
bull Ptrsquos without a thrombus on presentation (isolated HIT) have a risk of 50 for developing one
bull Is it prevalent
For patients receiving porcine UFH in therapeutic doses either by IV or subcutaneous (SC) for the treatment of venous or arterial thrombosis the risk of HIT has been estimated at approximately
1
Warkentin TE Greinacher A eds Heparin-induced thrombocytopenia 3rd ed 2004107-148 Marcel Dekker New York NY
bull What is HIT ndash Definitin ndash Subtypes ndash Pathophysiology ndash Clinical picture
bull When to suspect bull How to diagnose bull What to do
ndash Immediate management bull Before diagnosis bull After diagnosis
ndash Long term management bull Can heparin be used again bull Preventable disorder
Heparin Induced Thrombocytopenia
bull HIT
(heparin-induced thrombocytopenia) bull HAT
(heparin-associated thrombocytopenia)
HAT Syndrome
Non-immune heparin associated thrombocytopenia (HIT Type I)
bull Associated with an early (within 4 days) and usually mild decrease in platelet count (rarely lt100 x 109L)
bull Typically recovers within 3 days despite continued use of heparin
bull Nonimmunologic mechanisms (mild direct platelet activation by heparin)
bull Not associated with any major clinical sequelae bull Occurs primarily with high dose iv heparin
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
bull Is it prevalent
For patients receiving porcine UFH in therapeutic doses either by IV or subcutaneous (SC) for the treatment of venous or arterial thrombosis the risk of HIT has been estimated at approximately
1
Warkentin TE Greinacher A eds Heparin-induced thrombocytopenia 3rd ed 2004107-148 Marcel Dekker New York NY
bull What is HIT ndash Definitin ndash Subtypes ndash Pathophysiology ndash Clinical picture
bull When to suspect bull How to diagnose bull What to do
ndash Immediate management bull Before diagnosis bull After diagnosis
ndash Long term management bull Can heparin be used again bull Preventable disorder
Heparin Induced Thrombocytopenia
bull HIT
(heparin-induced thrombocytopenia) bull HAT
(heparin-associated thrombocytopenia)
HAT Syndrome
Non-immune heparin associated thrombocytopenia (HIT Type I)
bull Associated with an early (within 4 days) and usually mild decrease in platelet count (rarely lt100 x 109L)
bull Typically recovers within 3 days despite continued use of heparin
bull Nonimmunologic mechanisms (mild direct platelet activation by heparin)
bull Not associated with any major clinical sequelae bull Occurs primarily with high dose iv heparin
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
For patients receiving porcine UFH in therapeutic doses either by IV or subcutaneous (SC) for the treatment of venous or arterial thrombosis the risk of HIT has been estimated at approximately
1
Warkentin TE Greinacher A eds Heparin-induced thrombocytopenia 3rd ed 2004107-148 Marcel Dekker New York NY
bull What is HIT ndash Definitin ndash Subtypes ndash Pathophysiology ndash Clinical picture
bull When to suspect bull How to diagnose bull What to do
ndash Immediate management bull Before diagnosis bull After diagnosis
ndash Long term management bull Can heparin be used again bull Preventable disorder
Heparin Induced Thrombocytopenia
bull HIT
(heparin-induced thrombocytopenia) bull HAT
(heparin-associated thrombocytopenia)
HAT Syndrome
Non-immune heparin associated thrombocytopenia (HIT Type I)
bull Associated with an early (within 4 days) and usually mild decrease in platelet count (rarely lt100 x 109L)
bull Typically recovers within 3 days despite continued use of heparin
bull Nonimmunologic mechanisms (mild direct platelet activation by heparin)
bull Not associated with any major clinical sequelae bull Occurs primarily with high dose iv heparin
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
bull What is HIT ndash Definitin ndash Subtypes ndash Pathophysiology ndash Clinical picture
bull When to suspect bull How to diagnose bull What to do
ndash Immediate management bull Before diagnosis bull After diagnosis
ndash Long term management bull Can heparin be used again bull Preventable disorder
Heparin Induced Thrombocytopenia
bull HIT
(heparin-induced thrombocytopenia) bull HAT
(heparin-associated thrombocytopenia)
HAT Syndrome
Non-immune heparin associated thrombocytopenia (HIT Type I)
bull Associated with an early (within 4 days) and usually mild decrease in platelet count (rarely lt100 x 109L)
bull Typically recovers within 3 days despite continued use of heparin
bull Nonimmunologic mechanisms (mild direct platelet activation by heparin)
bull Not associated with any major clinical sequelae bull Occurs primarily with high dose iv heparin
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Heparin Induced Thrombocytopenia
bull HIT
(heparin-induced thrombocytopenia) bull HAT
(heparin-associated thrombocytopenia)
HAT Syndrome
Non-immune heparin associated thrombocytopenia (HIT Type I)
bull Associated with an early (within 4 days) and usually mild decrease in platelet count (rarely lt100 x 109L)
bull Typically recovers within 3 days despite continued use of heparin
bull Nonimmunologic mechanisms (mild direct platelet activation by heparin)
bull Not associated with any major clinical sequelae bull Occurs primarily with high dose iv heparin
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
HAT Syndrome
Non-immune heparin associated thrombocytopenia (HIT Type I)
bull Associated with an early (within 4 days) and usually mild decrease in platelet count (rarely lt100 x 109L)
bull Typically recovers within 3 days despite continued use of heparin
bull Nonimmunologic mechanisms (mild direct platelet activation by heparin)
bull Not associated with any major clinical sequelae bull Occurs primarily with high dose iv heparin
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
HIT (type II)
bull Transient prothrombotic disorder
bull Initiated by heparin
bull Thrombocytopenia caused by antibody-mediated platelet activation
bull Clinicopathological disorder
bull arterial and venous thrombi
bull Potential for development of life-threatening thromboembolic complications
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Whom to blame
Heparin and PF4
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
The PF4heparin antigenic complex bull PF4 is a highly cationic protein stored in platelet α
granules and released upon platelet activation bull PF4 binds to the negatively charged heparin through
electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
A Overall structure of the PF4fondaparinux complex Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer Monomers A B C and D in one PF4 tetramer are colored in green cyan magenta and yellow respectively B Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes A fragment of heparin first binds within the groove of one PF4 tetramer (limon left) binding of the first PF4 tetramer imparts a local linearized structure on heparin which enhances the binding of a second tetramer (pale green middle) and progression of this process eventuates in the formation of ultralarge antigenic complexes (right)
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
normal resting platelet platelet incubated with HIT serum
microparticles
Hughes M Blood 200096188-194
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Platelet activation in a patient with HIT
Kelton JG Chest 20051279S-20S
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Mechanisms of Thrombosis
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
The mechanism of hypercoagulability state is multifactorial bull in vivo platelet activation with formation of
procoagulant platelet-derived microparticles
caused by occupancy and cross-linking of platelet Fc receptors by formation of PF4heparinIgG immune complexes
bull expression of tissue factor on endothelial cells that have become activated because HIT antibodies recognize PF4 bound to endothelial heparan sulfate
bull expression of tissue factor by monocytes activated by HIT antibodies (HIT antibodies activate both platelets and monocytes primarily by FcγRIIA)
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
HIT - Pathogenesis
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
HIT-IgG remain not well understood bull Why not against heparan sulfate bull Rapidity (5 days) in the production of IgG
antibody bull Short persistence of antibody in patients
with HIT
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
HIT is a misdirected bacterial host defense
bull PF4 binds to bacteria and thereby exposes the epitope recognized by anti-PF4heparin antibodies which enhance phagocytosis of bacteria
bull Normal individuals have anti-PF4heparin antibodies in their plasma likely induced by minor bacterial inflammation such as periodontal disease
bull Under normal conditions the pathologic-activating capacities of these antibodies are likely quenched by scavengers but when the capacity of these proposed scavengers is overloaded for example after major surgery and treatment with heparin strong activation of platelets monocytes and endothelial cells result in a prothrombotic situation
Greinacher A Krauel K Jensch I Blood 2012120931-2
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Spontaneous HIT bull Not associated with
antecedent heparin exposure
bull Considered a true autoimmune manifestation caused by autoantibodies to PF4 heparin-like glycosaminoglycans (GAGs) complexes
Theodore E Warkentin et al Blood 20141233651-3654
(A) Clinical course (B) Thrombotic occlusion at internal carotid artery terminus (C) Flow reestablished to MCA (D) Reocclusion at origin of MCA (note the unusual problem of 5 rapid rethromboses may have been related to heparin administration during the mechanical thrombectomies) (E) Flow reestablished to MCA and anterior cerebral artery (after infusion of tissue-plasminogen activator) No heparin exposure occurred as a result of the platelet transfusions (platelets were prepared using citrate anticoagulant)
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Clinical Picture
bull Thrombocytopenia bull Thrombosis Venous gtgt Arterial (41)
bull Skin necrosis bull Acute systemic reaction following IV heparin bull DIC
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Thrombocytopenia
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Clinical course of patients
Girolami B Blood 15 April 2003 101(8)2955-2959
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Rapid-onset HIT
bull A large platelet count fall attributable to HIT antibodies within 24 h of starting heparin
bull Is not caused by an anamnestic immune response
bull Results from the administration of heparin to a patient who has already circulating HIT antibodies that resulted from a recent heparin exposure
bull Exposure within the past 100 days (and especially
within the last month) is associated with the phenomenon of rapid-onset HIT
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Profiles of HIT
67 30 rare
Patients received heparin within the past 100 days Previous exposure may have been minorunrecorded eg IV line flush
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
Warkentin TENEJM 348(11)1067-1069March 13 2003
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Thromboembolic Disorders Associated With HIT
bull Venous thrombosis ndash DVT ndash pulmonary embolism ndash cerebral sinus thrombosis ndash Adrenal vein thrombosis (adrenal hemorrhagic infarction)
bull Arterial thrombosis ndash Limb gangrene ndash cerebrovascular accident ndash MI ndash miscellaneous end-organ thromboses
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Skin Necrosis
Warkentin TE Br J Haematol 199692494ndash497
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Acute Systemic Reactions Caused by IV Heparin Bolus
bull The following can occur in patients sensitized to heparin within 5ndash30 minutes ndash Fever chills ndash Tachycardia hypertension ndash Flushing headache ndash Chest pain dyspnea ndash Nausea vomiting large-volume diarrhea ndash Transient global amnesia ndash Sudden ldquoanaphylactoidrdquo death
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Disseminated Intravascular Coagulation - DIC
bull Occurs in 5-15 of patients bull More common in delayed-onset HIT bull Prolongation of PTT complicates
monitoring of thrombin inhibitors bull Cancer-associated DIC with thrombosis
strongly resembles HIT
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Incidence of Complications and Mortality of HIT
Year No of
M F Age (year Complications Mortality
Patients range or SD) n () n ()
1983 62 34 28 19-93 38 (610) 14 (230)
1986 169 97 72 2-94 38 (225) 20 (120)
1996 127 60 67 670 +- 114 99 (780) 26 (205)
1996 dagger 62 33 29 667 +- 123 32 (516) 13 (210)
Includes patients initially presenting with thrombosis daggerSubgroup of the 127 patients presenting with thrombosis From Laster J Cikrit D Walker N Silver D Surgery 1987102763-770 and Warkentin TE Kelton JG Am J Med 1996101502ndash507
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Laboratory Testing for HIT
bull Platelet activation assays exploits the ability of HIT antibodies to activate normal platelets ndash serotonin release assay (SRA) ndash Aggregometry ndash heparin induced platelet activation (HIPA) ndash Flow cytometry
bull Antigen Assays ndash ELISA ndash HPF4-PaGIA (Diamed)
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
Iceberg Model
HIT associated Thrombosis
Thrombocytopenia
Activation Assays
Antigen Assays
Warkentin TE et al 199475-127
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
HIT - a clinicopathologic syndrome
bull Heparin use and thrombocytopenia are common events in hospitalized patients the combination does not necessarily indicate HIT
bull Nonpathogenic PF4heparin-reactive antibodies are a relatively common occurrence
in patients who have received heparin within the past days or weeks
HIT sepsis or both
Warkentin TE Chest 200512735S-45S
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
When Should HIT be Suspected
The four Trsquos
Lo GK Blood 2003102(suppl 1)535a
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
| Points (0 1 or 2 for each of 4 categories maximum possible score = 8) | |||||||
| 2 | 1 | 0 | |||||
| Thrombocytopenia | gt 50 fall or platelet nadir 20-100 | 30-50 fall or platelet nadir 10-19 | fall lt 30or platelet nadir lt 10 | ||||
| Clear onset between d 5-10 or less than 1 d (if heparin exposure within past 100 d) | Consistent with immunization but not clear (eg missing platelet counts) or onset of thrombocytopenia after d 10 | Platelet count fall too early (without recent heparin exposure) | |||||
| Thrombosis or other sequelae (eg skin lesions) | New thrombosis skin necrosis post heparin bolus acute systemic reaction | Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not yet proven | None | ||||
| Other cause for thrombocytopenia not evident | No other cause for platelet count fall is evident | Possible other cause is evident | Definite other cause is present | ||||
| Pretest probability score 6-8 = High 4-5 = Intermediate 0-3 = Low | |||||||
| First day of immunizing heparin exposure considered d 0 the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1-3 d more until an arbitrary threshold that defines thrombocytopenia is passed |
When should HIT be suspected
bull Platelet count falls by 50 +- a thrombotic event occurs between days 4 to 14 following initiation of heparin even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia have occurred
bull A proportional fall in platelet count of 50 is superior to an absolute threshold of 150 x 109L for the detection of HIT
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Choosing Wisely
bull Low probability 4ts score (0-3) was found to reliably exclude HIT in patients Low 4ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000)
bull Intermediate (4-5) and high (gt6) scores had poor positive predictive values for hit (014 ci 009-022) and (064 ci 040-082) respectively
bull The ldquochoosing wiselyrdquo campaign of the american society of hematology recommends against testing for hit in patients with a low pretest probability
bull 40 of patients evaluated by the 4ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Blood 2015126597-603
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Factors influencing The Frequency of HIT
bull UFHbovine lung gt porcine intestinal mucosa
bull UFH gt LMWH
bull Women gt men
bull Duration of Heparin ndash 5 days and more
bull Dose of Heparin High dose gt prophylaxis
bull Patient population Cardiac surgery other surgery trauma inflammation cancer infection
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Patient Population and Frequency of HIT
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Diagnostic and Initial Treatment
Algorithm
Arepally GM and Ortel TL N Engl J Med 2006 Rice L Arch Intern Med 20041641961-1964
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Treatment of Suspected HIT
bull Discontinue all heparin including ndash Heparin flushes ndash Heparin-coated pulmonary catheters ndash Heparinized dialysate and any other
medications or devices containing heparin bull Administer alternative anticoagulation bull Confirm diagnosis of HIT bull Monitor carefully for thrombosis bull Monitor platelet counts until recovery
Do not stop Heparin without administering alternative anticoagulation
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Treatment Paradoxes
bull Warfarin ndash increase risk of microvascular thrombosis
bull LMWH is contraindicated bull Prophylactic platelet transfusions ndash
relatively contraindicated bull Therapeutic doses of anticoagulant needed
even without thrombosis bull Re-exposure to heparin is possible after
antibodies have disappeared
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Gangrene of lower-limb digits
Warkentin TE 1Ann Int Med November 1997 | 127(9)804-812
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Alternative Anticoagulants to Heparin
Alving BM Blood 1 January 2003 Vol 101(1)31-37
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
bivalirudin bull A synthetic 20-amino acid peptide bull Appears to be promising as a treatment for HIT
based on case series bull Compared with lepirudin and argatroban
bivalirudin offers some significant pharmacologic advantages ndash short half-life ndash enzymic metabolism ndash low immunogenicity ndash minimal effect on INR prolongation
MoH Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Fondaparinux
bull A synthetic pentasaccharide
bull No cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays
bull Limited clinical experience in HIT patients
bull Development of HIT antibodies in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery equal to the rate of antibody formation in the group receiving enoxaparin none in either group developed clinical HIT
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1)
BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
adjunctive Treatments of HIT
bull IV immunoglobulin preparations of the IgG class (IVIG) success reported in a few cases
bull Plasmapheresis anecdotal experience only
bull AspirinClopidogrilGpIIbIIIa inhibitors
Serial SRA and IgG-specific anti-PF4 heparin EIA test results in relation to 4 therapeutic plasma exchange sessions performed on 4 consecutive days (last therapeutic plasma exchange performed 2 days before cardiac surgery using heparin)
Warkentin TE Sheppard JA Chu FV et al Blood 2015125195-8
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Typical Course of a Patient with HIT Treated with Danaparoid Sodium
5 10 12 14 17 22
Danaparoid
= Artificial respiration = Dialysis = Thromboembolus
Danaparoid Dalteparin Heparin
Plat
elet
s times
109 L
200
100
300
500 Heparin
Days Adapted from Greinacher A Drost W Michels I et al Ann Haematol 19926440ndash42
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Treatment of isolated HIT
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT
bull Simple discontinuation of heparin might avoid subsequent thrombosis ndash not true
bull Substantial risk for symptomatic thrombosis
among patients with isolated HIT ndash Objectively confirmed thrombosis 23-52 ndash Thrombotic death rates 45
bull Systematic duplex ultrasonography showed a 50 frequency of subclinical DVT
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Anticoagulation in isolated HIT
bull therapeutic-dose alternative anticoagulation bull continuing alternative anticoagulant until
platelet count recoveres to a stable plateau bull adding a short course of warfarin (following
platelet count recovery) provides additional protection against late HIT-associated thrombosis is unresolved
bull routine ultrasonography to identify silent venous thrombosis - could influence the duration of anticoagulant therapy
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Re-exposure of Heparin
bull Not enough data Therefore re-exposure to heparin is not generally advised But ndash No anamnestic immune response occurs in HIT ndash Among patients with rapid-onset HIT there is a strong
association with recent (lt 100 days) rather than
remote (gt 100 days) prior heparin exposure ndash When heparin has been accidentally or deliberately re-
administered when HIT antibodies were no longer present recurrence of HIT antibodies usually did not occur
bull Demonstrate that HIT antibodies are no longer detectable serologically before re-exposure
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Proportion of patients with heparin-dependent antibodies after an episode of HIT
Warkentin TE N Engl J Med 20013441286-1292
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Prevention of HIT
bull UFH derived from bovine lung is more likely to cause HIT and HIT antibody formation than UFH obtained from porcine gut
bull LMWH (enoxaparin) found a significantly reduced frequency of HIT in the patients receiving LMWH following hip replacement surgery (probably LMWH creates less ultra-large complexes (ULCs) with PF4)
Khandelwal S Lee GM Hester CG et al Blood 20161281789-99
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Avoid-Heparin Initiative Institution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
McGowan KE Makari J Damantouros A et al Blood 20161271954-9
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Early diagnosis of HIT Platelet counts - how often bull Diagnosis and early treatment of HIT to prevent
sequelae
bull Frequency of HIT among patients populations ndash Bovine UFH gt porcine UFH gt low molecular weight
heparin ndash Surgery gt medical gt pregnancy
bull Therapeutic-dose UFH - at least every-other-day platelet count monitoring until day 14
bull High risk (1-5) postoperative prophylaxis with UFH - at least every-other-day platelet count monitoring between postoperative days 4 to 14
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Platelet counts - how often bull Low risk (01-1)
ndash medicalobstetric patients receiving prophylactic-dose
UFH ndash postoperative patients receiving prophylactic-dose LMWH ndash postoperative patients receiving IV catheter UFH flushes ndash medicalobstetric patients receiving LMWH after first
receiving UFH platelet count monitoring every 2 to 3 days from day
4 to day 14 bull Very low risk (lt01) medicalobstetric patients
receiving LMWH or medical patients receiving only intravascular catheter UFH flushes - do not use routine platelet count monitoring
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
HIT ndash Take Home Message
bull An extreme prothrombotic diathesis bull Preventable bull Awareness bull A clinico-pathologic syndrome
ndash Clinical judgment ndash Knowing laboratory tests
Collaboration with lab is crucial for diagnosis and management of HIT
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
שמחפסח
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Laboratory assays for HIT antibodies
Warkentin TE Chest 200512735S-45S
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
HPF4 PaGIA test
Compared with ELISA reduced sensitivity better specificity Sensitivity and sensitivity are similar to functional assays
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Treatment of Thrombosis Complicating HIT Two DTIs
Adapted from Chest 2004126311S-337S
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Danaparoid Sodium ndash Orgaran
bull A low-molecular-weight heparinoid mixture of glucosaminoglycans (dermatan sulfate chondroitin sulfate) with a low degree of sulfation
bull predominant anti-factor Xa activity
bull Favorable results in ~90 of patients
bull Half-life of anti-factor Xa activity is ~25 hours disadvantage for patients who need surgical procedures
bull Cross-reactivity with heparin-dependent antibody in vitro is 10 to 20
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Treatment of Thrombosis Complicating HIT Danaparoid
Adapted from Chest 2004126311S-337S
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Anti Factor Xa Assay
bull Measures inhibition of activated factor X activity bull Useful for monitoring anticoagulants with primary
activity against factor Xa ndash UH ndash LMWH ndash Danaparoid
bull In use for LMWH activity in selected patients ndash Pregnant women ndash Renal failure ndash Children
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
platelet transfusions for HIT
bull petechiae and other mucocutaneous bleeding typical of thrombocytopenia are not clinical features of HIT despite severe thrombocytopenia
bull platelet transfusions relatively contraindicated for the prevention of bleeding in patients with acute HIT
bull if overt bleeding occurs platelet transfusions in the setting of possible or probable HIT may be appropriate
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
bull Institutionwide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855
to 49 cases per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Decision making when confronting possible heparin-induced thrombocytopenia
Rice L Arch Intern Med 20041641961-1964
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
Asher Winder MD Director Department of Hematology Wolfson Medical Center
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
bull clinical presentation bull new developments in the pathogenesis bull clinical diagnostic strategies for HIT bull emerging therapeutics in the management of HIT
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
HIT ndash Heparin induced thrombocytopenia
bull iatrogenic complication of UFH or LMWH therapy bull caused by antibodies that recognize complexes of platelet factor 4 (PF4) and
heparin within 5 to 14 days of drug exposure bull In some sensitized patients high-titer anti-PF4heparin antibodies of the
immunoglobulin G (IgG) isotype bind FcγRIIA receptor bearing cells trigger cellular activation and elicit a profound hypercoagulable state
bull may result in arterial andor venous thrombosis
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
The PF4heparin antigenic complex
bull PF4 is a highly cationic protein stored in platelet α granules and released upon platelet activation
bull PF4 binds to the negatively charged heparin through electrostatic interactions leading to the generation of ultra-large complexes
bull Neo-epitopes are expressed on PF4heparin only when PF4 binds to heparins of chain length gt11 saccharides
bull heparin stabilizes the PF4 molecule in its tetrameric conformation and in the process linearizes itself allowing additional PF4 tetramers to join the growing complex and exposing neo-epitopes on PF4 recognized by HIT antibodies
bull Inhibition of tetramer formation using a monoclonal antibody to the PF4 monomer interferes with heparin and HIT antibody binding pointing the way to development of therapeutic targets
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Crystal structure of the PF4heparin complex and formation of ultra-large complexes
Cai Z et al Nat Commun 201568277 Onwuemene O amp Arepally GM Hematology 20162016262-268
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
PF4heparin immune response
bull innate immune mechanisms caused either by bacterial infection andor antigen-mediated complement activation may contribute significantly to the development of anti-PF4heparin antibodies
bull a correlation of periodontal disease with anti-PF4heparin antibody reactivity bull interactions of PF4 with both gram-positive and gram-negative bacteria as well
as to short chain polyphosphates released from platelets bull direct complement activation by PF4heparin complexes resulting in antigen
binding to complement receptor 2CD21 on B cells Because antigen binding to CD21 significantly enhances immunogenicity these studies implicate CD21-mediated binding of PF4heparin complexes as an initial step for subsequent antibody formation
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Mechanisms of thrombosis
bull HIT antibodies activate both platelets and monocytes primarily by FcγRIIA and confirm prior observations on the contribution of monocytes to tissue factor expression and thrombin generation
bull In addition to direct platelet FcγRIIA signaling by HIT antibodies monocyte-derived thrombin provides additional platelet signaling via cleavage of protease-activated receptor 110 Depletion of monocytes or inhibition of FcγRIIA signaling markedly impairs platelet aggregation and fibrin deposition in this experimental system thus providing an explanation for the intense thrombin generation seen in association with HIT
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Visualization of thrombus formation by a HIT-like monoclonal antibody
Oluwatoyosi Onwuemene and Gowthami M Arepally Hematology 20162016262-268
copy2016 by American Society of Hematology
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Updates in HIT epidemiology
bull Anti-PF4heparin antibodies are rare in healthy individuals In 2 large surveys of healthy donors (n = 40297) and blood bank donors (n = 380011) anti- PF4heparin antibodies were detected in sim3 to 4 of patients using a low cutoff for antibody positivity (optical density [OD] gt04) and in 03 to 05 of healthy subjects using a higher cutoff for antibody positivity (OD gt1)
bull anti-PF4heparin autoantibodies may develop in the context of inflammation andor orthopedic surgery
bull surgical inflammation may provide sufficient inflammatory signals for triggering PF4heparin antibody formation in the absence of heparin
bull In this prospective study of sim2000 patients who were either treated with pharmacologic or mechanical compression seroconversion rates were high in patients receiving only mechanical prophylaxis sim15 in patients receiving dynamic compression vs 65 for static compressions
Bito S Miyata S Migita K et al Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4heparin antibody formation after orthopedic surgery Blood 2016127(8)1036-1043
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Updates in disease presentation
bull The hallmark of HIT is the development of a mild to moderate absolute (50-70 times 109L) or relative thrombocytopenia (platelet count fall of gt30 to 50) which develops 5 to 14 days after heparin exposure and a median of 2 days after development of anti-PF4heparin antibodies1718 in heparin-naiumlve individuals
bull In patients with more proximate heparin exposure (lt100 days) thrombocytopenia can develop acutely within 24 hours due to the presence of circulating anti-PF4heparin antibodies
bull Thrombocytopenia as the only manifestation of HIT is termed ldquoisolatedrdquo HIT ldquoIsolatedrdquo HIT is considered a prothrombotic condition due to high rates of subsequent thrombosis (20 to 50)
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
clinical variants of HIT delayed-onset HIT and spontaneous HIT
bull autoimmune features due to occurrence of antibodies that bind PF4 and heparin-like glycosaminoglycans (GAGs)
bull described in case reports andor series the incidence remains poorly defined bull Antibodies causing delayed-onset HIT are usually cross-reactive with PF4GAG
complexes found on cell surfaces and characteristically elicit heparin-independent platelet activation in functional assays
bull Spontaneous HIT is not associated with antecedent heparin exposure and is considered a true autoimmune manifestation caused by autoantibodies to PF4GAG complexes
bull All the reported cases to date are associated with findings of thrombocytopenia and thrombosis in association with high-titer platelet activating anti-PF4heparin antibodies
bull As with delayed-onset HIT anti-PF4heparin antibodies bind to PF4GAGs on platelets and thus have the distinctive feature of heparin-independent platelet activation
bull Diagnostic criteria for spontaneous HIT have been proposed based on clinical findings of thrombocytopenia and thrombosis without prior heparin exposure
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Updates in diagnosis
bull a combination of clinical and laboratory criteria bull Clinical features rely on showing a temporal association of heparin therapy with
thrombocytopenia andor thrombosis and excluding other causes of thrombocytopenia
bull The 4Ts clinical scoring system is a valuable clinical prediction rule for patients suspected of HIT
bull In a recent meta-analysis low probability 4Ts score (0-3) was found to reliably exclude HIT in patients Low 4Ts scores were associated with a high negative predictive value (NPV) (0998 95 confidence interval [CI] 0970-1000) intermediate (4-5) and high (gt6) scores had poor positive predictive values for HIT (014 CI 009-022) and (064 CI 040-082) respectively
bull 40 of patients evaluated by the 4Ts will have intermediate or high clinical scores that require additional laboratory testing to establish diagnosis
bull Based on these findings the ldquoChoosing Wiselyrdquo campaign of the American Society of Hematology recommends against testing for HIT in patients with a low pretest probability
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Is ldquoChoosing Wiselyrdquo wise enough
bull In a prospective multicenter study 526 patients suspected of HIT were assessed with a 4Ts score a rapid particle assay (PF4H-PaGIA) and serotonin release assay (SRA) and managed based on the results of a 4Ts score and the rapid particle assay while awaiting the results of the SRA
bull Of the 321 patients with a low pretest score 6 of were SRA+ (19 of low score cohort)
bull Review of these 6 cases assigned to a ldquolow scorerdquo indicated that 2 patients were incorrectly scored and 4 cases were complex patients in whom concurrent causes of thrombocytopenia were present
bull clinicians should assign a ldquolow scorerdquo with certainty if there is uncertainty regarding the clinical criteria then patients should be assigned higher points to merit an intermediate level of suspicion
Linkins LA Bates SM Lee AY Heddle NM Wang G Warkentin TE Combination of 4Ts score and PF4H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia prospective cohort study Blood 2015126(5)597-603
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Reference Design N
Pretest probability of 4Ts Posttest probability of 4Ts (+ assayminus assay)
Low (0-3) Intermediate (4-5)
High (6-8) Low (0-3) Intermedi
ate (4-5) High (6-
8)
Nellen V Single center retrospective 1291 08 14 53 NR 650 950
Leroux D Multicenter prospective 380 21 11 47 11
006 42
04 83
26
Linkins LA
Multicenter prospective 526 19 7 37 150 420 880
EIA enzyme immunoassay NR not reported
Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
Nellen V ET al Haematologica 201297(1)89-97 Leroux D et al Br J Haematol 2014166(5)774-782
Linkins LA et al Blood 2015126(5)597-603
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
emerging therapies for HIT
bull The direct thrombin inhibitors (DTI) argatroban and bivalirudin are US Food and Drug Administration-approved agents for the treatment of HIT (argatroban) and use in HIT patients undergoing percutaneous coronary intervention or cardiac surgery (bivalirudin) Use of either agent should be guided by the half-life of therapeutic agent and co-existing hepatic andor renal dysfunction For discussion of the safety and efficacy of parenteral nonheparin anticoagulants in the management of HIT the reader is referred to recent guidelines and reviews4042
bull DTI alternatives such as fondaparinux and emerging therapies such as the direct oral anticoagulants (DOACs) are clinically appealing because they have
bull fondaparinux does not cross-react with HIT antibodies bull In a minority of patients fondaparinux has been reported to cause HIT
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Direct oral anticoagulants (DOACs)
bull Rivaroxaban use in HIT has been reported in a small number of case reports 1 case series51 and a multicenter single arm prospective study52 The latter prospective single arm study closed early due to poor enrollment52 but reported outcomes on 22 enrolled patients 12 of whom were diagnosed with HIT In this small cohort of HIT patients rivaroxaban appeared to be safe and effective with 910 thrombocytopenic patients achieving full platelet count recovery during therapy Although there were no newrecurrent thromboses or bleeding complications in patients diagnosed with HIT some complications were noted including the progression of a previously diagnosed catheter-associated thrombosis in 1 patient amputation being required for another patient with worsening ischemia and major bleeding occurring gt1 week after drug discontinuation in another patient In a case series by Sharifi et al 11 patients were initially treated with a parenteral DTI followed by rivaroxaban The authors reported no recurrent arterial or venous thrombosis or bleeding complications in this cohort However a lack of study details and heterogenous treatment assignment limit conclusions from this study51 Other than the case series reported by Sharifi et al51 there are only case reports on the use of apixaban and dabigatran for HIT (Table 2)51dArr-53
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Direct oral anticoagulants (DOACs) Reference Study (N) HIT Dx DOAC Dose (mg) Other AC Outcomes
Sharifi M Case series (22)
ELISASRA+ (20) Dabigatran (6) 150 twice daily
Initial argatroban
New DVT (5)
Clinical Dx (2) Rivaroxaban (11) 20 daily SVT (2)
mdash Apixaban (5) 5 twice daily Deaths (6)dagger
Linkins LA Prospective cohort (12) SRA+ Rivaroxaban 15 twice daily rarr
20 daily
Initial fondaparinux (6) VTE (1)
Transitioned to fondaparinuxDagger (1) BKA (1)
Deaths (4)dagger
Major bleedingDagger (1)
Ng HJ Case series (3) ELISA+ Rivaroxaban 15 twice daily rarr 20 daily
Transitioned to warfarin (1)
Platelet recovery no thrombosis
AC anticoagulant BKA below-knee amputation DVT deep vein thrombosis DX diagnosis SVT supraventricular tachycardia VTE venous thromboembolism Retrospective case series with prospective determination of outcomes daggerDeaths were not due to thrombosis but to the underlying disease states including cancer heart failure renal failure systemic sclerosis sepsis and end-stage chronic obstructive pulmonary disease DaggerOne patient transitioned to fondaparinux due to elevated hepatic enzymes sectRenal-adjusted dose in a dialysis-dependent patient Sharifi M et al Thromb Res 2015135(4)607-609
Linkins LA et al J Thromb Haemost 201614(6)1206-1210 Ng HJ et al Thromb Res 2015135(1)205-207
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
prevention of rather than early recognition and treatment of HIT
Avoid-Heparin Initiative bull institutionwide strategy of replacing unfractionated heparin (UFH) with low-
molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
bull a single tertiary-care hospital in Toronto Canada bull Rates of HIT were compared in the pre-intervention (2003-2005) and
postintervention (2007-2012) phases bull The annual incidence of suspected cases of HIT decreased from 855 to 49 cases
per 10000 admissions (relative risk reduction [RRR] 42 plt0001) The annual incidence of adjudicated cases of HIT decreased from 107 to 22 per 10000 admissions (RRR 79 plt0001) The annual incidence of adjudicated cases of HIT with thrombosis decreased from 46 to 04 per 10000 admissions (RRR 907 plt0001)
bull While the authors additionally reported a cost savings in HIT-related expenditures with implementation of their Avoid-Heparin Initiative this analysis did not account for the higher unit cost of LMWH compared with UFH3 and is thus subject to further scrutiny
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-
Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
P lt 001 for each comparison
bullThe Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT adjudicated HIT HITT and associated costs
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- The Paradox
- Slide Number 3
- An extreme prothrombotic diathesis
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Heparin Induced Thrombocytopenia
- HAT Syndrome
- HIT (type II)
- Whom to blame
- The PF4heparin antigenic complex
- Slide Number 13
- Scanning electron micrographs of resting platelets and platelets activated with HIT serum in the presence of heparin
- Platelet activation in a patient with HIT
- Mechanisms of Thrombosis
- The mechanism of hypercoagulability state is multifactorial
- HIT - Pathogenesis
- HIT-IgG remain not well understood
- HIT is a misdirected bacterial host defense
- Spontaneous HIT
- Clinical Picture
- Thrombocytopenia
- Clinical course of patients
- Rapid-onset HIT
- Profiles of HIT
- Delayed-Onset Heparin-Induced Thrombocytopenia (HIT) after Exposure to a Single Dose of Heparin
- Thromboembolic Disorders Associated With HIT
- Skin Necrosis
- Acute Systemic Reactions Caused by IV Heparin Bolus
- Disseminated Intravascular Coagulation - DIC
- Incidence of Complications and Mortality of HIT
- Laboratory Testing for HIT
- Iceberg Model
- HIT - a clinicopathologic syndrome
- When Should HIT be Suspected
- When should HIT be suspected
- Choosing Wisely
- Factors influencing The Frequency of HIT
- Patient Population and Frequency of HIT
- Diagnostic and Initial TreatmentAlgorithm
- Treatment of Suspected HIT
- Treatment Paradoxes
- Gangrene of lower-limb digits
- Alternative Anticoagulants to Heparin
- bivalirudin
- Fondaparinux
- Direct oral anticoagulants (DOACs)
- adjunctive Treatments of HIT
- Slide Number 50
- Treatment of isolated HIT
- Anticoagulation in isolated HIT
- Re-exposure of Heparin
- Proportion of patients with heparin-dependent antibodies after an episode of HIT
- Prevention of HIT
- Avoid-Heparin InitiativeInstitution-wide strategy of replacing unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for both therapeutic and prophylactic indications
- Early diagnosis of HITPlatelet counts - how often
- Platelet counts - how often
- HIT ndash Take Home Message
- Slide Number 60
- Slide Number 61
- Laboratory assays for HIT antibodies
- HPF4 PaGIA test
- Treatment of Thrombosis Complicating HIT Two DTIs
- Danaparoid Sodium ndash Orgaran
- Treatment of Thrombosis Complicating HIT Danaparoid
- Anti Factor Xa Assay
- platelet transfusions for HIT
- avoid-heparin initiative Prevention rather than early recognition and treatment of HIT
- Decision making when confronting possible heparin-induced thrombocytopenia
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia new mechanisms amp novel therapies
- HIT ndash Heparin induced thrombocytopenia
- The PF4heparin antigenic complex
- Slide Number 75
- PF4heparin immune response
- Mechanisms of thrombosis
- Slide Number 78
- Updates in HIT epidemiology
- Updates in disease presentation
- clinical variants of HITdelayed-onset HIT and spontaneous HIT
- Updates in diagnosis
- Is ldquoChoosing Wiselyrdquo wise enough
- Pre- and posttest probability of HIT using a combined approach of the 4Ts and EIAs
- emerging therapies for HIT
- Direct oral anticoagulants (DOACs)
- Direct oral anticoagulants (DOACs)
- prevention of rather than early recognition and treatment of HITAvoid-Heparin Initiative
- Annual incidence of suspected HIT positive HIT assay adjudicated HIT and HITT per 10thinsp000 admissions 2003-2005 and 2007-2012
-