Heparin induced thrombocytopenia Hank Ng 9/26/18

Learning Objectives Definition Pathogenesis Risk Factors Evaluation and Diagnosis Management

HIT Prothrombotic adverse drug effect Type 1 Type 2 Nadir 100,000 Timing first 2 days Direct effect on platelet aggregation Not associated with thrombosis Don’t have to discontinue heparin Type 2 PF4/antibodies Increased risk of thrombosis – heparin induced thrombocytopenia and thrombosis (HITT) IgG antibodies form quickly over days

Ddx of thrombocytopenia Disseminated intravascular coagulation (DIC) Immune thrombocytopenia (ITP) Thrombotic microangiopathy (TMA) – TTP, HUS Drug-induced thrombocytopenia Systemic lupus erythematosus (SLE) Antiphospholipid Syndrome (APS)

PF4 on platelets binds to heparin and forms a neoantigen Individuals with HIT Ab bind the PF4/heparin complex – platelets get activated Thrombocytopenia – caused by removal of IgG coated platelets of reticuloendothelial system Unlike other drug induced thromocytopenia – HIT activates platelets and aggregation causes thrombosis

Incidence 0.2-5% of patients treated with heparin Risk Factors UFHvs LMWH Meta analysis of 15 studies comparing incidence of HIT (thrombocytopenia and +HIT Ab) predominantly orthopedic patients found UFH 2.6% vs LMWH 0.2% absolute risk Another meta analaysis 13 studies 5,275  patients for medical VTE treatment with HIT diagnosed by Hit Ab showed no difference in UFH vs LMWH Older age (rare <40) and therapeutic doses (0.76% vs <0.1%)

Considering HIT Thrombocytopenia Thrombosis Average nadir 60,000 Counts rarely drop below 20,000 Thrombosis Venous (20-50%) > arterial (3-10%) Rarer complications Limb gangrene - usually venous Necrotizing skin lesions Adrenal v. thrombosis and hemorrhage Stroke, MI, organ infarction Anaphylaxis, systemic reaction

Timing Most common 5-10 days Early onset – within 24 hrs Patient exposed to heparin previously in the past 100 days with circulating antibodies

Evaluation: 4T Score

Intrepretation 0-3 points = low probability 4 to 5 points = Intermediate probability 6 to 8 points = High probability Meta-analysis over 3000 patients with clinically suspected HIT Negative predictive value with low HIT score .098 PPV for intermediate 0.14 and high 0.64

Diagnostic score for heparin‐induced thrombocytopenia after cardiopulmonary bypass Example of platelet time courses from 2 distinct patients. Representation of one pattern A (biphasic pattern, solid triangles), characterized by a fall in the platelet count more than 4 days after CPB (the initial fall immediately after CPB is followed by a rise within 5 days and then by a further fall) and one pattern B (open circles), characterized by post‐CPB thrombocytopenia persisting beyond day 4. Platelet counts are reported until the index date (first day of suspected HIT, arrows). IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Diagnostic score for heparin‐induced thrombocytopenia after cardiopulmonary bypass, Volume: 2, Issue: 11, Pages: 1882-1888, First published: 10 November 2004, DOI: (10.1111/j.1538-7836.2004.00949.x)

Retrospective French study looking at 84 patients suspected HIT Variables Score Platelet count time course Pattern A 2 Pattern B 1 Time from CPB to index date ≥ 5 days < 5 days CPB duration ≤ 118 min > 118 min Total score Classification High probability of HIT ≥ 2 Low probability of HIT < 2 Retrospective French study looking at 84 patients suspected HIT NPV 97% Identified 34/35 HIT cases

Diagnosis HIT antibody testing Immunoassay: ELISA Detects presence of anti- (PF4)/heparin antibodies in patient serum ELISA: add patient serum to plate coated with PF4/heparin – add another Ab to test Functional: test the ability of HIT antibodies from patient serum to activate test platelets SRA: Normal test platelets are radiolabeled with 14C-serotonin and incubated with patient serum plus heparin at therapeutic or excessive concentrations. A positive test is the release of 14C-serotonin when therapeutic heparin concentrations are used (0.1 units/mL) Heparin-induced platelet activation (HIPA): platelets /platelet-rich plasma (PRP) from healthy donors is added to serum of patient and platelet activation is measured in the absence of heparin and in the presence of low and high heparin concentrations. A positive test shows minimal platelet activation in the absence of heparin and in the presence of high heparin concentrations (eg, 10 to 100 units/mL) and strong activation in the presence of low heparin concentrations HIPA tests platelet aggregation

ELISA OD < 0.4, rules out HIT OD > 2.0 for intermediate probability 4T score or OD > 1.5 for high probability 4T score rules in HIT

Management Stop heparin Reverse warfarin Argatroban (direct thrombin) Use in renal insufficiency maintain the aPTT at 1.5 to 3 times baseline Bivalirudin (direct thrombin), off label Use in renal/hepatic insufficiency aPTT 1.5 to 2.5 times baseline Danaparoid (heparnoid) – not available in the US monitor anti-Xa - adjust to 0.5-0.8 Fondaparinux - synthetic pentasaccharide – inhibits Xa Direct oral anticoagulants – observational studies Small review 12 pts – no new thrombosis or major bleeding

Further Management Once HIT confirmed Lower extremity U/S Thrombosis – anticoagulation for 3 months (ASH and ACCP guidelines No thrombosis – anticoagulation for 1 month One review of 127 patients with diagnosed HIT found risk of 30 day thrombosis without anticoagualtion was 53% Platelets should recover in 7 days

oral anticoagulants Warfarin DOAC start when PLT > 150,000 and stably anticoagulated with another agent 5 day overlap recommended DOAC overlap with IV anticoagulants for dabigatran or edoxaban

Cardiac or vascular surgery Test for PF4/heparin antibodies If not present – can get heparin day of surgery, but avoid pre and post op heparin If antibodies present and heparin needed during surgery – plasmapheresis or IVIG

Sources Cuker A, Gimotty PA, Crowther MA, et al: Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 120:4160-7, 2012 Lillo-Le Louet A, Boutouyrie P, Alhenc-Gelas M, et al: Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. Journal of Thrombosis and Haemostasis 2:1882- 1888, 2004 Warkentin TE, Kelton JG: A 14-year study of heparin-induced thrombocytopenia. Am J Med 101:502-7, 1996