Heparin-induced thrombocytopenia a diagnostic and therapeutic challenge

Transcription

1 Heparin-induced thrombocytopenia a diagnostic and therapeutic challenge Christopher M Ward Northern Blood Research Centre Royal North Shore Hospital Royal North ShoreHospital ISTH Bangkok November 2017 Sydney Medical School

2 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 Consultant Major Stockholder No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare Speakers Bureau Honoraria Scientific Advisory Board Alexion, Amgen, Bayer, Boehringer Ingelheim, Celgene, IL, Pfizer-BMS, Sanofi Amgen, Bayer, Boehringer Ingelheim, Celgene, GSK, IL, Janssen, Novartis, Pharmacia, Specialised Therapeutics Alexion, 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 ISTH Advanced Training Course Dubai, UAE

3 When good drugs turn bad. Paradoxical effects of an anticoagulant

4 HITS remains a diagnostic and clinical challenge What is HIT? Clinical features of HIT Laboratory testing screening assays - functional assays Treatment options

5 Heparin-induced Thrombocytopenia/Thrombosis Heparin-dependent antibodies (recognise heparin-pf4) Antibodies not uncommon?10% 1-5% develop thrombocytopenia - after several days Watch 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 anticoagulant DO NOT USE warfarin until platelets recovered

6 Thrombosis Thrombocytopenia 5% exposed Heparin-dependent antibodies?5% of popn

7 HITTS : pathogenesis Heparin Anti-heparin/PF4 Abs PF4 Platelet clearance Thrombosis Heparans PF4 Endothelium

8 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?

9 Is HIT a misdirected immune response? PF4-glycan forms a neoepitope Adaptive immune response B Infection: Platelets release PF4 PF4 binds surface glycans on bacteria Antibodies to PF4- glycan produced, enhance phagocytosis Antibodies cross-react with PF4- heparin HIT Krauel et al Blood 2011 Heparin PF4 Subsequent exposure to heparin and platelet activation

10 HITS remains a diagnostic and clinical challenge What is HIT? Clinical features of HIT Laboratory testing screening assays - functional assays Treatment options

11 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%)

12 Delayed diagnosis of HIT is not uncommon... TKJR Adrenal Haem. PE HIT Ab +ve Dia + Agg - Dia - Agg + Clexane 40mg/d UFH/Clexane Danaparoid

13 Skin lesions in HIT can include local necrosis at sites of heparin injection

14 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

15 4T Pretest Probability Score for HIT Low 0-3, Intermediate 4-5, High 6-8 Warkentin et al Br J Haematol 2003

16 Clinical utility of 4T score: a metaanalysis 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 4T N.B. 13 of these patients had a positive functional test... Negative predictive value (95% CI ) Positive predictive value of intermediate 4T 0.14 ( ) Positive predictive value of high 4T (8%) 0.64 ( ) Low probability 4T appears... a robust means of excluding HIT Interassessor variability and no standard assay used Cuker et al Blood 2012

17 Timing of platelet fall after surgery and heparin typical patterns of HIT A: typical, gradual fall on heparin after 5-10 days B: acute fall, often with systemic reaction C: delayed onset, fall in platelets after heparin ceased Warkentin and Greinacher Ann Thorac Surg 2003

18 Thrombosis in HITTS can occur at low-normal platelet counts Warkentin Semin Hematol 1998

19 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 procoagulant response, macro- and microvascular thrombosis) Warkentin J Thromb Haemost 2011

20 Autoimmune HIT: a puzzling entity 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 Warkentin & Greinacher Curr Opin Hematol 2016

21 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

22 Diagnosis and management of HIT a work in progress

23 Why is HIT over-diagnosed? Thrombocytopenia is common in hospitalised patients, 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

24 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

25 HITS remains a diagnostic and clinical challenge What is HIT? Clinical features of HIT Laboratory testing screening assays - functional assays Treatment options

26 The iceberg model of HIT Warkentin Hematology (ASH) 2011

27 Anti-Heparin-PFA immunoassays PaGIAs (Diamed) qualitative assay, simple and rapid Serum or plasma similar False negatives higher than EIAs, many false positives ELISA assays (GTI, Stago, Hyphen) heparin-pf4 or polyvinylsulfate-pf4 as target antigen highly sensitive but high false positive rates (incl APL) semiquantitative, expensive usually batched improve 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

28 PaGIA assay for Heparin-PF4 antibodies (Diamed) Particle gel immunoassay Rapid test, convenient Previous issues with assay quality, many false positives

29 Clinical laboratory algorithm to predict HIT 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 Ruf et al Thromb Haemost 2011

30 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

31 HITS remains a diagnostic and clinical challenge What is HIT? Clinical features of HIT Laboratory testing screening assays - functional assays Treatment options

32 HIT functional assays Antibodies 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 IU/ml 100 IU/ml

33 Why perform a functional assay? 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

34 Functional assays for HITS (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

35 The way forward. a faster path to confirming HIT

36 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

37 Multiplate test cell single use test cell with twin impedance sensor sample volume 0.3 ml/test firm adhesion and aggregation of platelets on the sensor surface enhances the electrical resistance between the 2 sensor wires

38 HIMEA assay to detect platelet-activating HIT antibodies 1 U/mL 200 U/mL Negative Strong positive Weak positive False positive Morel-Kopp et al J Thromb Haemost 2016

39 Clinical suspicion of HIT -?4T score Cease heparin exposure Screening immunoassay for PF4- heparin IgG specific preferred negative positive HIT excluded resume heparin HIT possible change anticoagulant HIT more likely if high OD negative? Functional assay to confirm HIT

40 HITS remains a diagnostic and clinical challenge What is HIT? Clinical features of HIT Laboratory testing screening assays - functional assays Treatment options

41 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)

42 Alternative anticoagulants in HITS now Lepirudin Danaparoid Fondaparinux Argatroban Bivalirudin direct thrombin inhibitor heparinoid pentasaccharide direct thrombin inhibitor direct thrombin inhibitor In future dabigatran, rivaroxaban, apixaban?

43 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

44 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 - - -

45 Fondaparinux newer options 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 + +

46 Anticoagulation in HIT Necessary until platelets have normalised Prophylactic 750U BD sc danaparoid or 2.5mg fondaparinux if no thrombosis Therapeutic consider danaparoid infusion (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

47 Diagnosis and management of HIT Functional 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 APTTbased 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

48 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

49 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

50 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 Ab positive cases Caution with alternate anticoagulants do not start warfarin too early and avoid platelet transfusion