heparin-induced thrombocytopenia …a diagnostic and

Royal North ShoreHospital

Heparin-induced thrombocytopenia

…a diagnostic and therapeutic challenge

Christopher M Ward

Northern Blood Research Centre Royal North Shore Hospital

ISTH Bangkok November 2017SydneyMedicalSchool

ISTH Advanced Training CourseDubai, UAE

Disclosures for Christopher Ward In compliance with COI policy, ISTH requires the following disclosures to the session audience:

Research Support/P.I. Bayer, CSL, Pharmion

Employee No relevant conflicts of interest to declare

Consultant No relevant conflicts of interest to declare

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau Alexion, Amgen, Bayer, Boehringer Ingelheim, Celgene, IL, Pfizer-BMS, Sanofi

HonorariaAmgen, Bayer, Boehringer Ingelheim, Celgene, GSK,

IL, Janssen, Novartis, Pharmacia, SpecialisedTherapeutics

Scientific Advisory BoardAlexion, Amgen, Astra-Zeneca, Bayer, Boehringer

Ingelheim, Celgene, GSK, IL, Janssen, Pfizer-BMS, Sanofi, Specialised Therapeutics

Presentation includes discussion of the following off-label use of a drug or medical device:

HIT testing using Multiplate aggregometer, alternate anticoagulants for HIT

When good drugs turn “bad”….

Paradoxical effects of an anticoagulant

HITS remains a diagnostic and clinical challenge

What is HIT?

Clinical features of HIT

Laboratory testing – screening assays

- functional assays

Treatment options

Heparin-induced Thrombocytopenia/Thrombosis

Heparin-dependent antibodies (recognise heparin-PF4)Antibodies not uncommon ?10%

1-5% develop thrombocytopenia - after several daysWatch for significant drops within normal range

Thrombosis in 10-20% (HITTS) with high morbidity/mortality

Venous > arterial, also skin necrosis at injection sites

Increased risk with His131 FcR polymorphism

Diagnosis must be clinical, poor assay sensitivity

STOP heparin treat with alternative anticoagulantDO NOT USE warfarin until platelets recovered

Thrombosis

Thrombocytopenia

Heparin-dependentantibodies ?5% of popn

5% exposed

HITTS : pathogenesis

Endothelium

Heparin

PF4

HeparansPF4

ThrombosisPlatelet clearance

Anti-heparin/PF4 Abs

Why is HIT an unusual immune response?

Rapid appearance of PF4-heparin antibodies

Most are IgG rather than IgM

PF4-heparin antibodies present in those not exposed to heparin, and asymptomatic – high prevalence after cardiothoracic surgery

PF4-heparin antibodies do not persist – failure of memory B cells?

Is HIT a misdirected immune response?

Heparin

PF4

Infection:Platelets release PF4

PF4 binds surface glycans on bacteria

B

PF4-glycan forms a neoepitope

Antibodies to PF4-glycan produced, enhance phagocytosis

Subsequent exposure to heparin andplatelet activation

Antibodies cross-react with PF4-heparin

Adaptive immune response

HIT

Krauel et al Blood 2011


What is HIT?



- functional assays

Treatment options

Clinical events associated with HIT...

Venous thrombosis (30-70%) – DVT or PE

Adrenal necrosis/haemorrhage

Cerebral sinus thrombosis

Venous limb gangrene (esp with VKA)

Arterial thrombosis (15-30%) incl limb gangrene

Stroke or myocardial infarction

Skin lesions at injection sites (10%), skin necrosis

Acute reactions to iv heparin (10%)

DIC (10%)

HIT Ab +ve

Dia +Agg -

Dia -Agg +TKJR

Clexane 40mg/d

UFH/Clexane

Adrenal Haem.

PE

Delayed diagnosis of HIT is not uncommon...

Danaparoid

Skin lesions in HIT

can include local necrosis at sites of heparin injection

Digital gangrene is one of the most striking complications of HIT

High rates of limb amputation in many series

Reflects acute arterial thromboembolism

Can be triggered by addition of warfarin – adds PC, PS depletion to the hypercoagulable state

“4T” Pretest Probability Score for HIT

Warkentin et al Br J Haematol 2003Low 0-3, Intermediate 4-5, High 6-8

Clinical utility of 4T score: a metaanalysis

Cuker et al Blood 2012

Systemic review of literature – 13 studies included both 4T and reference “standard” (SRA, HIPA or platelet aggregation) in 3068 patients

55.8% (1712) classified as low probability by 4TN.B. 13 of these patients had a positive functional test...Negative predictive value 0.998 (95% CI 0.97-1.00)

Positive predictive value of intermediate 4T 0.14 (0.09-0.22)

Positive predictive value of high 4T (8%) 0.64 (0.40-0.82)

“Low probability 4T appears... a robust means of excluding HIT”Interassessor variability and no standard assay used

Timing of platelet fall after surgery and heparin –typical patterns of HIT

Warkentin and Greinacher Ann Thorac Surg 2003

A: typical, gradual fall on heparin after 5-10 daysB: acute fall, often with systemic reactionC: delayed onset, fall in platelets after heparin ceased

Thrombosis in HITTS can occur at low-normal platelet counts

Warkentin Semin Hematol 1998

Uncommon variants of HIT

“Spontaneous” HIT without heparin exposure –may occur postop, after infection

Delayed-onset HIT – triggered by potent “autoimmune-like” antibodies activating platelets in the absence of heparin. Higher morbidity/mortality and prolonged time to platelet recovery

HIT-associated consumptive coagulopathy – DIC causing problems if therapy is monitored by APTT

Coumarin necrosis – caused by extreme hypercoagulability (platelet procoagulantresponse, macro- and microvascular thrombosis)

Warkentin J Thromb Haemost 2011

“Autoimmune HIT: a puzzling entity

Warkentin & Greinacher Curr Opin Hematol 2016

Some patients develop “autoimmune” strong antibodies that activate platelets in vitro and in vivo without heparin being present

Can be detected in functional assays by platelet aggregation in the “no heparin” control

Leads to “delayed onset HIT” – begins or worsens after stopping heparin, or “persistent HIT” – low platelets for more than 30d after stopping heparin, or even “spontaneous” HIT with a typical clinical and laboratory picture but no heparin exposure…

Believed due to PF4 binding to non-heparin platelet glycosaminoglycans, including chondroitin sulfate, triggering “heparin-PF4” antibodies

Practice point

When should we suspect HIT?

Unexpected drop in platelet count (but may remain in normal range) in a patient with current or recent heparin exposure

Most common in “sick” patients, where platelets are activated by sepsis, inflammation, surgery – rarely seen in routine prophylaxis or pregnancy

Occurs after LMWH as well as UFH

Diagnosis and management of HIT

… a work in progress

Why is HIT over-diagnosed?

Thrombocytopenia is common in hospitalisedpatients, especially in ICU

(LMW) heparin use is widespread in this group

Heparin-PF4 antibodies have a high prevalence in older patients, esp after cardiothoracic surgery

BUT...most Ab positive patients do not have true HIT

Why does it matter?

A putative diagnosis of HIT mandates a switch to alternative anticoagulants

These anticoagulants are expensive, difficult to use and expose patients to higher risks of bleeding (esp the direct thrombin inhibitors)

Patients with this diagnosis may have to use alternative anticoagulants longterm

Overdiagnosis of HIT is putting many patients at unnecessary risk... and markedly increasing treatment costs


What is HIT?



- functional assays

Treatment options

Warkentin Hematology (ASH) 2011

The “iceberg” model of HIT

PaGIAs (Diamed)qualitative assay, simple and rapidSerum or plasma similarFalse negatives higher than EIAs, many false positives

ELISA assays (GTI, Stago, Hyphen)heparin-PF4 or polyvinylsulfate-PF4 as target antigenhighly sensitive but high false positive rates (incl APL)semiquantitative, expensive – usually batchedimprove specificity with IgG-specific cf. IgGAM, OD>1.00

Nanoparticle flow - STic (Stago)Rapid immunoassay designed for fresh samples

Rapid automated assays – HemosIL HIT-Ab (IL)Potential for similar performance to ELISA, but on demand

Anti-Heparin-PFA immunoassays

PaGIA assay for Heparin-PF4 antibodies (Diamed)

Particle gel immunoassay

Rapid test, convenient

Previous issues with assay quality, many “false positives”

Clinical–laboratory algorithm to predict HIT

Ruf et al Thromb Haemost 2011

Combined algorithm for HIT diagnosis – incorporates 4T score, ELISA and OD value

Patients with a 4T score >3 and OD>1.0 were considered positive

Tested against a retrospective cohort of 83 patients (9 SRA positive) – algorithm indicated DTI therapy in 22 patients

Sensitivity of algorithm was 90%, specificity of 82% - better than 4T alone, or ELISA alone

Practice point

When should we test for HIT?

Clinical picture (including 4T score) cannot make the diagnosis, score is less reliable in medical and ICU patients

Need access to a rapid “screen” assay or ELISA

Think before ordering assays in those with a high likelihood of heparin-PF4 antibodies (e.g. post-cardiothoracic surgery)

Negative screening assay is useful in excluding HIT – but a positive result will lead to a change in therapy


What is HIT?



- functional assays

Treatment options

HIT functional assaysAntibodies only bind to stoichiometric PF4-heparin complexes:→ Heparin must be stopped the day before blood collection for functional investigation

Functional assays must include low and high heparin concentrations

PRP 0.5 IU/ml 100 IU/ml

Washed platelets 0.1 - 0.2 IU/ml 100 IU/ml

Thrombocytopenia in hospitalised patients is very common AND(LMW) heparin use in hospitalised patients is very common

Hep-PF4 antibodies are common – most are “false positive”True HIT, with platelet activation is uncommon

A positive functional assay mandates alternate anticoagulation, ?indefinitely

A negative functional assay provides more options –e.g. transient heparin for bypass in a frail patient

Why perform a functional assay?…

(Light transmission aggregometry)Better performance from washed platelet assays:

Serotonin release assay (SRA) Warkentin

Heparin-induced platelet aggregation (HIPA) Greinacher

Whole-blood impedance aggregometry (HIMEA) Morel-Kopp

(Flow cytometry for platelet activation)

(Thrombin generation)Tan et al Semin Thromb Haemost 2012

Functional assays for HITS

The way forward….

… a faster path to confirming HIT

Consensus method paper using whole-blood impedance aggregometry to detect platelet activating HIT antibodies

A rapid, non-radioactive alternative to serotonin release assay –does require HIT-sensitive donor platelets

Functional assay to distinguish “true” HIT from false positive samples

single use test cell with twin impedancesensor

sample volume0.3 ml/test

firm adhesion and aggregation of platelets on the sensor surface enhances the electrical resistance between the 2 sensor wires

Multiplate® test cell

HIMEA assay to detect platelet-activating HIT antibodies

Negative False positive

Weak positive

Strong positive

1 U/mL

200 U/mL

Morel-Kopp et al J Thromb Haemost 2016

HIT excluded –resume heparin

Cease heparin exposure

HIT possible – change anticoagulant

negative positive

Clinical suspicion of HIT - ?4T score

Screening immunoassay for PF4-heparin – IgG specific preferred

Functional assay to confirm HITnegative?

HIT more likely if high OD


What is HIT?



- functional assays

Treatment options

Key principles of therapy in HIT

Cease all exposure to heparin(s)

Avoid platelet transfusion

Anticoagulation is required to counter hypercoagulable state – prophylactic if no thrombosis, therapeutic if thrombosis

Continue alternate anticoagulant until platelet count normalised

Defer warfarin until platelet count normalised (at least 5 days)

Alternative anticoagulants in HITS – now…

Lepirudin direct thrombin inhibitor

Danaparoid heparinoid

Fondaparinux pentasaccharide

Argatroban direct thrombin inhibitor

Bivalirudin direct thrombin inhibitor

In future… dabigatran, rivaroxaban, apixaban?

The ideal anticoagulant for HIT would have…

Flexible dosing prophylactic and therapeutic

SC option allow outpatient treatment

Assay to monitor allows dose adjustments

Not affect INRs to simplify switch to warfarin

Stable dosing

Short half-life many patients are unstable

Non-renal clearance

Low bleeding risk

Low cost

The conventional options…Danaparoid Hirudins Argatroban

Flexible dosing + + +

SC option + - -

Assay to monitor + +? +?

Not affect INRs + -- ?

Stable dosing + - ?

Short half-life - + +

Non-renal cl. - --- +

Low bleeding risk ? -- ?

Low cost - - -

newer options…Fondaparinux NOACs

Flexible dosing + +

SC option + - (PO)

Assay to monitor +? +

Not affect INRs + ?

Stable dosing + +

Short half-life - -

Non-renal cl. - ?

Low bleeding risk ? ?

Low cost + +

Anticoagulation in HIT

Necessary until platelets have normalised

Prophylactic – 750U BD sc danaparoid or 2.5mg fondaparinux if no thrombosis

Therapeutic – consider danaparoidinfusion (monitor anti-Xa) or 7.5mg fondaparinux

Direct thrombin inhibitors (hirudins) may have higher bleeding risk – caution with dosing and renal impairment

NOACs an unproven alternative…

Diagnosis and management of HITFunctional assays (e.g. SRA) are superior to immunoassays in identifying clinically relevant heparin-induced Abs;

A positive functional assay makes a definitive diagnosis of HIT

Only ~10% of suspected HIT are Ab positive; of those with positive PF4 immunoassays, only10-50% are functional positive

Recommend use of danaparoid or fondaparinux(indirect thrombin inhibitors) rather than DTIs because :

• proven effective in HIT, also in non-HIT thrombosis, • available in prophylactic and therapeutic doses, weight-adjusted• monitor with anti-Xa levels (less risk of over/underdosing than APTT-based monitoring of lepirudin, argatroban), • longer half-lives, easier to overlap with warfarin• likely lower bleeding rates than DTIs (cf inappropriate dosing of lepirudin in the literature)

Warkentin Hematology (ASH) 2011

Practice point

Alternate anticoagulants in HIT?

Simple if no thrombosis – cover with fondaparinux, danaparoid or NOAC, at least until platelets recovered

Patients with thrombosis are often unstable and complex – prefer parenteral options such as danaparoid or argatroban

Caution with monitoring, especially when transitioning to warfarin – bleeding risks are high with direct thrombin inhibitors

Growing clinical experience with NOACs, but little published to date. If using rivaroxaban or apixaban, start with higher dose as per acute VTE

Avoid warfarin until platelets fully recovered, no progressive thrombosis

Can we re-expose HIT patients to heparin?

Blood 2016

HIT antibodies are usually transient

If a patient with prior HIT needs bypass or other high-risk procedure, they can be briefly exposed to heparin again (provided heparin-PF4 antibodies are negative)

Very low risk of recurrence, even though antibodies will be induced

Cover postoperative course with an alternative anticoagulant

HIT : a continuing challenge

Most thrombocytopenia on heparin is not HIT, but always consider the diagnosis

Clinical features can be helpful – but laboratory testing is needed to either exclude or confirm “true” HIT

Consider functional testing to confirm Abpositive cases

Caution with alternate anticoagulants – do not start warfarin too early and avoid platelet transfusion

heparin-induced thrombocytopenia …a diagnostic and

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