HEPARIN-INDUCED THROMBOCYTOPENIA

HEPARIN INDUCED THROMBOCYTOPENIA (HIT)1Who gets itHow and why they get itHow to recognize itHow to treat itHEPARIN-INDUCED THROMBOCYTOPENIAUnfractionated heparin (UFH) (beef > pork)Continuous iv infusionCardiopulmonary bypassLow dose sqHeparin flushesHeparin-bonded cathetersLow molecular weight heparinMore likely to cause HIT if pt previously exposed to UFH

Causative agents2Most cases associated with administration of UFH for treatment or prophylaxisHEPARIN-INDUCED THROMBOCYTOPENIAIsolated thrombocytopenia (Isolated HIT)Arterial or venous thrombosis (HITT)DVT, PE, MI, stroke, peripheral arterial occlusionDIC, microangiopathic hemolytic anemiaSkin necrosis (at injection sites or distant)

Venous limb gangrene (? Role of warfarin)Sudden deathARDSHemorrhagic adrenal infarctionClinical manifestations

HEPARIN-INDUCED THROMBOCYTOPENIAUFH > LMWH >> FondaparinuxDuration of heparin treatment 6 daysRarely occurs in patients < 40 years old2-3 fold higher incidence in womenSurgical > medical > obstetric patientsIncidence in trauma patients proportional to severity of traumaRelated to degree of platelet activation?EpidemiologyBlood 2012; 119: 2209HEPARIN-INDUCED THROMBOCYTOPENIAPresenting with thrombosis (n=65)Presenting with no thrombosis (n=62)Total (n=127)Age67 10.766.7 12.367.0 11.4Male/Female27/3833/2960/67SURGICAL PTS513384 (66.1%) Orthopedic251540 Cardiovascular10919 Oncology7613 General628 Neurosurgery314MEDICAL PTS142943 (33.9%) Cardiac61016 DVT or PE4711 Other41216Incidence and presenting featuresWarkentin and Kelton, Am J Med 1996;101:5025In retrospective studies, HIT most often recognized in surgery pts, esp ortho surgery? Because they are at higher risk for thrombosis to start withTHROMBOTIC COMPLICATIONS IN HITType of thrombosisPts presenting with thrombosis (n=65)Pts presenting with only thrombocytopenia (n=62)VENOUS (n=78)5424 DVT (n=61)4021 New3521 Progression40 Recurrence10PE (n=32)266 New255 Recurrence11ARTERIAL (n=18)126 Limb72 Myocardial infarct31 Thrombotic stroke23Other (n=3)12 Sudden death01 Adrenal hemorrhage11 NO THROMBOSIS (n=30)NA30Am J Med 1996;101:5026Most thromboses venousPts diagnosed with isolated HIT have high likelihood of subsequent thombosisISOLATED HIT IS ASSOCIATED WITH A HIGH RISK OF SUBSEQUENT THROMBOSIS

Am J Med 1996;101:502Over 50% of patients presenting with isolated HIT had a subsequent thrombotic episode within 30 daysSubstitution of warfarin for heparin after the onset of thrombocytopenia did not prevent thrombosis 7Caveat: retrospective study, potential for diagnostic selection biasBut it seems clear from this and other studies that isolated HIT does create a very high risk for subsequent thrombosis

UNFRACTIONATED HEPARIN IS MORE LIKELY TO CAUSE HIT THAN LMWHRandomized trial in pts having hip surgeryWarkentin et al, NEJM 1995;332:133083-4% incidence of HIT in hip surgery, probably the highest risk group

Warkentin et al, NEJM 1995;332:1330THE FREQUENCY OF THROMBOSIS AFTER HIP SURGERY IS MUCH HIGHER IN PATIENTS WITH HIT THAN IN THOSE WITHOUT HITOdds ratio for thrombosis 37 times higher in HIT pts

All cases in patients receiving UFH as prophylaxisHIT associated with 40-fold increase in risk of thrombosisTHE HIT INCIDENCE IN MEDICAL PATIENTS TREATED WITH LOW DOSE SQ UFH IS ABOUT 2%Girolami et al, Blood 2003;101:295510But medical pts at substantial risk as wellLMWH IS MORE LIKELY TO CAUSE HIT IN PATIENTS WITH PRIOR UFH EXPOSUREPrandoni et al, Blood 2005;106:3049Prospective cohort study, 1754 medical pts0.8% overall incidence of HIT 0.3% incidence if no prior UFH exposure1.7% incidence if prior UFH exposureAll cases in first 2 weeksPrevalence of thromboembolism 16.6x higher in patients with HIT (29% vs 2.4%)11Incidence of HIT in pts getting LMWH after prior exposure to UFH roughly comparable to incidence with UFHDevelopment of HIT antibodies is more common in major surgery than minor surgery, and more common with UFH than LMWHResults of a prospective trial

Lubenow, N. et al. Blood 2010;115:1797-1803Warkentin et al, NEJM 1995;332:1330

THROMBOSIS IN HIT MAY OCCUR WITH NORMAL PLATELET COUNT

********Warkentin et al, NEJM 1995;332:1330THE PLATELET COUNT DROPS PRIOR TO THROMBOSIS IN HIT *Thrombotic episode14Platelet count normally rises steadily for at least a week after hip surgery. Note that all pts with HIT and normal plts had at least two days of dropping plts before thrombotic event

Recent heparin exposure may cause rapid onset HITWarkentin and Kelton, NEJM 2001;344:128615HIT virtually never happens less than 4 days after starting heparin UNLESS there has been prior exposure to heparin

Rapid-onset HIT is associated with re-exposure to heparin within 90 daysWarkentin and Kelton, NEJM 2001;344:128616And this exposure usually has been within a month, almost always within 3 months

Heparin-dependent antibodies usually disappear within 90 days an episode of HITWarkentin et al, NEJM 1995;332:133017Because the antibodies that cause the problem disappear during this time period functional assay being more predictive of the conditionDELAYED ONSET HITDescribes 14 patients treated with heparin, discharged, and later re-hospitalized with thromboembolism and positive tests for HIT antibodiesMost patients got heparin during cardiac surgery12/14 had mild thrombocytopenia (66-145K) at time of thrombotic episodeMedian time between discharge and readmission 14 days, maximum 40 days11 patients re-treated with heparin: all had clinical deterioration and worsening thrombocytopenia3 patients diedAnn Intern Med 2002;136:21018We have said that HIT can occur without thrombocytopenia. It can also occur when a patient is no longer getting heparin. This is a particularly difficult form of HIT to diagnose, and the consequences of not diagnosing it can be direPATHOPHYSIOLOGY OF HITHIT IS CAUSED BY ANTIBODIES AGAINST A HEPARIN-PLATELET FACTOR 4 COMPLEXPlatelet membraneFC receptorFabFCAntibody binding to platelet FC receptor activates platelet41PF4Activated plateletsecretes PF42HeparinPF4 binds heparin3Antibody binds heparin-PF4 complex20Heparin-induced thrombocytopenia: Platelet factor 4 (PF4) released by activated platelet. This binds heparin, creating a potential neoantigen. Antibody binds the complex of heparin-PF4. The antigen antibody complex then binds to the FC receptor on another platelet, causing platelet activation. This may account for the association between HIT and thrombosis in some patients. PATHOPHYSIOLOGY OF HITWarkentin, Brit J Haematol 2003;121:535Heparin-PF4 complexes stimulate antibody productionAg-Ab complex binds to and activates platelets, monocytesSize of immune complex is critical, varies with PF4 and heparin concentrationsInhibited by high heparin concentrationsActivated platelets release procoagulant microparticlesActivated monocytes produce tissue factorAntibodies may cross-react with PF4 bound to endothelial cell heparan sulfate vessel wall injurySome HIT antibodies can activate platelets in the absence of heparinHeparin concentration affects the size and charge of heparin:PF4 complexes and their ability to activate plateletsBlood 2007;110:4253

Low heparin:PF4 ratio small complexesHigh heparin:PF4 ratio small complexes1:1 heparin:PF4 large complexesCharge of complexesHeparin conc

Smaller heparin molecules less platelet activation by HIT antibodiesNEJM 2013;368:737

Clinical factors may help determine the likelihood of developing HITHealthy volunteers given heparin or LMWH make IgM antibodies to heparin/PF4Pathologic HIT antibodies are usually IgGConcomitant immune stimulus necessary to promote IgG HIT antibody formation?Higher PF4 levels after surgery or acute illness may promote formation of larger immune complexesFormation of DNA-PF4 complexes following tissue injury may initiate immune response, antibodies can cross-react with heparin-PF4 complexesBlood 2007;110:4253J Thromb Haemost 2012;10:1446Blood 2013;122:272HIT Antibodies can activate platelets in the absence of heparin

J Thromb Haemost 2005;3:2168Why is HIT so different from other immune-mediated drug reactions?Disease featurePossible explanationHigher incidence after surgery or traumaMore platelet activation and PF4 release more/larger immune complexes Higher incidence with unfractionated heparinLarger heparin molecules larger immune complexesParadoxical thrombosisActivation of platelets & monocytes by immune complexesOnset may follow heparin discontinuationDamage to endothelial cells by antibodies bound to PF4/heparan sulfate complexes?Heparin-independent antibodies?Lack of recurrence with heparin re-exposureComplex pathophysiology, antibody formation necessary but not sufficient to cause clinical diseaseDIAGNOSIS OF HITDISTINGUISHING IMMUNE FROM NON-IMMUNE HEPARIN INDUCED THROMBOCYTOPENIAMany patients have a transient decrease in platelets within 24 hours of receiving heparin. This is not an antibody-mediated effect and not associated with thrombosisHow can it be distinguished from HIT?By the time courseBy the clinical pictureBy serology and other lab tests28

Median platelet nadir 55K15% had nadir >150K (diagnosed because platelet count fell more than 50% or because of clinical events)The severity of thrombocytopenia did not predict thrombotic eventsSevere thrombocytopenia is rare in HITWarkentin, Brit J Haematol 2003;121:5352915% are not thrombocytopenic at all. Rarely does plt count drop below 20KNo connection between severity of thrombocytopenia and clinical courseClincal features that favor a diagnosis of HIT

Blood 2012;119:220930Thrombocytopenia usually but not always present and typically not severe

The 4 T score predicts a positive HIT antibody testJ Thrombos Haemost 2006;4:759Score% Testing positive534%31A corollary more likely to get false + test if 4T score low so dont order test willy-nilly

LABORATORY DIAGNOSIS OF HITImmunoassay for heparin-PF4 antibodies (EIA)Very high sensitivity, rapid turnaroundHigh positive results typical of HITTRapid bedside assayMany false positive results, not recommendedC14 Serotonin release assay (SRA)Measures heparin-dependent platelet activationBest predictor of thrombotic riskLimited availability (Blood Center of SE Wisconsin), slower turnaround

A positive EIA test in a patient with a low pre-test probability of HIT according to 4T rule is likely to be a false positive32ELISA a very good screening test and its all you need if the clinical picture fitsConsider SRA when clinical picture cloudy or when risk of giving alternative anticoagulant highThe serotonin release assay predicts thrombosis in HIT

SRA and EIA positiveSRA and EIA negativeEIA positive, SRA negativeAm J Hematol 2007;82:1037Warkentin, Brit J Haematol 2003;121:535The incidence of HIT antibody formation and risk of HIT varies among different patient populationsThe Iceberg model

34Cardiac patients have high incidence of serologic abnormalities but low incidence of clinical HITOrtho patients getting UFH have highest risk of clinical HIT

J Thrombos Haemost 2004;2:2133-7A STRONGLY POSITIVE EIA RESULT IS ASSOCIATED WITH HIGHER RISK OF SUBSEQUENT THROMBOSIS

OD values in HIT vs HITT patientsThrombosis-free survival vs OD35We dont routinely report OD hereThe dilemma of HIT testing in critically ill patientsMost critically ill patients receive heparin productsUp to 20% have at least one clinical criterion for HITOnly about 1% actually develop HITPrediction rules (4T score, etc) do not function well in this patient population

A diagnosis of HIT in a critically ill patient should always be confirmed by SRA testingCrowther et al, Blood 2011;118:198TREATMENT OF HITTREATMENT OF HITDiscontinue all heparin, including flushesLMWH may cross-react with HIT antibodies, should not be usedIf thrombosis present: give alternative thrombin inhibitorConsider treating even if thrombosis absent (high risk of thrombosis in patients with isolated HIT)Treatment alternatives:Direct inhibitorsLepirudinBivalirudin (little data, but approved for HIT patients having PCI)ArgatrobanDabigatran?Indirect inhibitorsFondaparinux Do not give warfarin (risk of venous gangrene)DIRECT THROMBIN INHIBITORSArgatroban (Novastan)Synthetic arginine derivativeClearance mainly hepatic (can use in renal failure); halflife 40-50 minGiven by continuous iv infusion, monitoring aPTTCoagulopathic patients (long baseline aPTT) difficult to monitorNo antidoteNo data yet for oral thrombin and Xa inhibitors39Most of the data on the efficacy of these drugs is on lepirudinArgatroban therapy in HITPooled data from 2 prospective non-randomized trialsHazard ratio with argatroban 0.3 vs historical controlsNo difference in major bleeding vs controls

Chest 2006;129:1407ARGATROBAN IN HITACCP RECOMMENDATIONSBolus: NoneContinuous infusion:Normal organ function: 2 mcg/kg/monLiver dysfunction, post cardiac surgery, anasarca: 0.5-1.2 mcg/kg/monAdjust aPTT to 1.5-3.0 x baselineCheck aPTT q 4hArgatroban prolongs PT/INR, making transition to warfarin trickyFONDAPARINUX (Arixtra) Synthetic polysaccharide, inhibits factor Xa preferentiallyDoes not typically cross-react with HIT antibodiesLong half-life (17-20 h), no antidoteSQ administrationMonitoring unnecessaryNot FDA-approved for HIT treatment

Rare reports of fondaparinux-associated HIT (NEJM 2007; 356:2653)Fondaparinux appears to be effective and safe in patients with HITReferenceNNew thrombosisMajor BleedingKuo & KovacsThromb Haemost 200550/50/5Lobo et alThromb Haemost 200770/70/7Grouzi et alClin Appl Thromb Haemost 2009240/240/24Pooled Data360/360/36Warkentin, Hematol Oncol Clin N Am 2010; 24:755

VENOUS GANGRENEArch Intern Med 2004;164:6644Tissue deathStarting warfarin too soon in HIT may promote this processWARFARIN MAY PROMOTE VENOUS GANGRENE IN HITRetrospective review of 158 cases of HIT8/8 patients with venous limb gangrene treated with warfarin, vs 3/10 with arterial thrombosis (p=.004)Median INR 5.8 in patients with venous gangrene vs 3.1 in those who did not (p 50% during heparin administration, or if new thrombotic event occurs within 2-3 weeks of heparin exposureOnset may be earlier if there was prior exposure to heparin within past 100 daysOnset may follow discontinuation of heparinLMWH rarely causes HIT but may perpetuate itRisk of thrombosis in HIT is high even if patient does not have thrombosis at time of diagnosisSUMMARY-2HIT is caused by production of antibodies to heparin-PF4 complex that activate plateletsHIT is unlikely if tests for heparin-PF4 antibodies are negativePatients with HIT should generally be treated with a thrombin or Xa inhibitor other than heparin or LMWHWarfarin treatment should be delayed until platelet count is normal