Heparin-Induced Thrombocytopenia (HIT)

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1 Heparin-Induced Thrombocytopenia (HIT) Joshua Ononuju, Pharm. D. Owensboro Medical Health Systems

2 Objectives Overview Pathogenesis Risk factors Clinical Presentation and Diagnosis Treatment goals and options Nouveau Drugs

3 Overview of HIT An immune-mediated ADR Associated with thrombocytopenia Transient prothrombic disorder Antibodies can last up to 85 days

4 Pathogenesis Platelet factor 4 binds to UFH Conformational change leads to antibody formation UFH-PF4 antibodies activate platelets

5 Pathogenesis Levy JH. Heparin-Induced Thrombocytopenia, a prothrombic disease. Hematol Oncol Clin North Am. Feb 2007; 21(1): 66

6 Warkentin TE. Heparin-Induced Thrombocytopenia. Hematol Oncol Clin North Am. Aug 2007; 21(4): 591

7 Warkentin TE. Heparin-Induced Thrombocytopenia. Hematol Oncol Clin North Am. Aug 2007; 21(4): 591

8 Levy JH. Heparin-Induced Thrombocytopenia, a prothrombic disease. Hematol Oncol Clin North Am. Feb 2007; 21(1): 68

9 Clinical Presentation Thrombocytopenia 50% drop from baseline or platelet count x<150 x 10 9 Thrombosis DVT and PE have highest incidence

10 Other Presentations Anaphylactoid reaction Skin lesions at injection site Venous limb gangrene Caused by coumadin therapy Disseminated Intravascular Coagulation (DIC)

11 4 T s: Likelihood of HIT Warkentin TE. Heparin-Induced Thrombocytopenia. Hematol Oncol Clin North Am. Aug 2007; 21(4): 596

12 Laboratory Tests Platelet activation tests SRA: Serotonin release Assay Antigen assays EIA: Enzyme Immunoassay

13 Laboratory Tests Can confirm the presence of UFH-PF4 antibodies Poor correlation between presence of antibodies and risk of thrombosis Lab tests alone cannot predict clinical HIT

14 Iceberg Model Warkentin TE. Heparin-Induced Thrombocytopenia. Hematol Oncol Clin North Am. Aug 2007; 21(4): 591

15 Treatment Goals and Options

16 Treatment goals To prevent thrombosis if HIT is suspected To treat acute thrombotic complications due to suspected HIT and prevent further thrombosis To safely anticoagulate high risk patients with a history of HIT

17 Do s and Don ts Warkentin TE. Heparin-Induced Thrombocytopenia. Hematol Oncol Clin North Am. Aug 2007; 21(4): 599

18 Treatment Options Direct Thrombin Inhibitors Warfarin Danaparoid Fondaparinux

19 Direct Thrombin Inhibitors Lepirudin Argatroban Bivalirudin* MOA: Directly inhibits thrombin No antidote for overdose *Not FDA approved for HIT treatment

20 DTI Overview Levy JH. Heparin-Induced Thrombocytopenia, a prothrombic disease. Hematol Oncol Clin North Am. Feb 2007; 21(1): 74

21 Lepirudin Associated with increased bleeding at FDA recommended doses Most studies have recommended the maintenance dose without the initial bolus may decrease bleeding risk 50% of patients develop antibodies after administration

22 Warfarin MOA: inhibits the production of vitamin K dependent clotting factors Hepatically metabolized Narrow therapeutic range Therapy should began after platelet count is above 150 x 10 9 Venous limb gangrene Dose should began at 5mg/day

23 Bridging therapy DTIs can increase INR along with warfarin Argatroban has the strongest influence on INR Overlap therapy of at least 5 days INR x>4 before stopping DTI

24 Danaparoid (Orgaran) Not FDA approved for HIT Not commercially available in the USA Several studies have shown efficacy in acute HIT thrombosis and prophylaxis

25 Danaparoid (Orgaran) Non-heparin Factor Xa and IIa inhibitor Renally cleared: 24hr half-life No specific antidote: Protamine sulfate? Cross reactivity with HIT antibodies Use favored by positive outcomes in HIT worldwide

26 Danaparoid (Orgaran) Dose 2250 Units IV bolus Then 400 Units/hr IV x 4hrs 300 units/hr IV x 4 hrs 200 units/hr IV Dose adjusted by anti-xa levels Range anti-xa units/ml

27 Danaparoid (Orgaran) Bolus dose is weight based: X<60kg-1500 units 75-90kg-3000 units X>90kg-3750 units

28 Fondaparinux Pentasaccharide derivative of heparin MOA: Factor Xa inhibition Lowest risk of causing HIT Possible cross reactive to HIT antibodies Possible treatment option

29 Bauer K. New Anticoagulants. Hematology Am Soc Hematol Educ Program. 2006:453 Comparison of Heparin Derivatives

30 Treatment Strategies HIT Thrombosis Prophylaxis: Argatroban and warfarin therapy 3-6 months depending on risk HIT Thrombosis: Lepirudin or Argatroban and warfarin therapy for 3-6 months Danaparoid and warfarin therapy for 3-6 months* *Not FDA approved

31 Nouveau Treatment options Dabigatran etexilate Idraparinux Rivaroxaban

32 Dabigatran etexilate Oral DTI Prodrug for dabigatran Renally excreted: hr half-life Proposed once a day dosing In Phase III trials for prevention and treatment of VTE

33 Idraparinux Hypermethylated analogue of fondaparinux High affinity for factor Xa 80 hr half-life 2.5mg SC q weekly proposed dose for stroke prevention in AF and acute VTE No antidote Chemically similar agent with a specific antidote is in trials now

34 Rivaroxaban Oral factor Xa inhibitor 5-9 hr half life In Phase III trials

35 Summary HIT is a clinicopathologic syndrome Timing is important Risks of HIT and presentations vary Remember the 4 T s Assess treatment options based on liver and renal function Argatroban vs. Lepirudin

36 References Bauer K. New Anticoagulants. Hematology Am Soc Hematol Educ Program. 2006:450-6 Levy JH. Heparin-Induced Thrombocytopenia, a prothrombic disease. Hematol Oncol Clin North Am. Feb 2007; 21(1): Maistre E, Gruel Y and Dominique Lasne. Diagnosis and management of heparin-induced thrombocytopenia. Canadian Journal of Anesthesia. 2006;53.6:s123-s134 Warkentin TE. Heparin-Induced Thrombocytopenia. Hematol Oncol Clin North Am. Aug 2007; 21(4):

37 References Warkentin TE. Think of HIT. Hematology Am Soc Hematol Educ Program. 2006: Warkentin TE, Greinacher A et al. Treatment and Prevention of Heparin-Induced Thrombocytopenia. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines(8 th ed.). June 2008:s340-s380

38 Questions???

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