HeparinInduced Thrombocytopenia HIT

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Heparin-Induced Thrombocytopenia (HIT)

• Joshua Ononuju, Pharm. D.
• Owensboro Medical Health Systems

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Objectives

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

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Overview of HIT

• An immune-mediated ADR
• Associated with thrombocytopenia
• Transient prothrombic disorder
• Antibodies can last up to 85 days

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Pathogenesis

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

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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 xlt150 x
  109
• Thrombosis
• DVT and PE have highest incidence

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Other Presentations

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

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4 Ts Likelihood of HIT

• Warkentin TE. Heparin-Induced Thrombocytopenia.
  Hematol Oncol Clin North Am. Aug 2007 21(4) 596

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Laboratory Tests

• Platelet activation tests
• SRA Serotonin release Assay
• Antigen assays
• EIA Enzyme Immunoassay

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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

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Iceberg Model

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

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Treatment Goals and Options
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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

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Dos and Donts

• Warkentin TE. Heparin-Induced Thrombocytopenia.
  Hematol Oncol Clin North Am. Aug 2007 21(4) 599

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Treatment Options

• Direct Thrombin Inhibitors
• Warfarin
• Danaparoid
• Fondaparinux

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Direct Thrombin Inhibitors

• Lepirudin
• Argatroban
• Bivalirudin
• MOA Directly inhibits thrombin
• No antidote for overdose
• Not FDA approved for HIT treatment

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DTI Overview

• Levy JH. Heparin-Induced Thrombocytopenia, a
  prothrombic disease. Hematol Oncol Clin North
  Am. Feb 2007 21(1) 74

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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

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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 109
• Venous limb gangrene
• Dose should began at 5mg/day

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Bridging therapy

• DTIs can increase INR along with warfarin
• Argatroban has the strongest influence on INR
• Overlap therapy of at least 5 days
• INR xgt4 before stopping DTI

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Danaparoid (Orgaran)

• Not FDA approved for HIT
• Not commercially available in the USA
• Several studies have shown efficacy in acute HIT
  thrombosis and prophylaxis

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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

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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 0.5-0.8 anti-Xa units/mL

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Danaparoid (Orgaran)

• Bolus dose is weight based
• Xlt60kg-1500 units
• 75-90kg-3000 units
• Xgt90kg-3750 units

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Fondaparinux

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

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Comparison of Heparin Derivatives

• Bauer K. New Anticoagulants. Hematology Am Soc
  Hematol Educ Program. 2006453

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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
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Nouveau Treatment options

• Dabigatran etexilate
• Idraparinux
• Rivaroxaban

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Dabigatran etexilate

• Oral DTI
• Prodrug for dabigatran
• Renally excreted 14-17 hr half-life
• Proposed once a day dosing
• In Phase III trials for prevention and treatment
  of VTE

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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

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Rivaroxaban

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

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Summary

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

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References

• Bauer K. New Anticoagulants. Hematology Am Soc
  Hematol Educ Program. 2006450-6
• Levy JH. Heparin-Induced Thrombocytopenia, a
  prothrombic disease. Hematol Oncol Clin North
  Am. Feb 2007 21(1) 65-88
• Maistre E, Gruel Y and Dominique Lasne.
  Diagnosis and management of heparin-induced
  thrombocytopenia. Canadian Journal of
  Anesthesia. 200653.6s123-s134
• Warkentin TE. Heparin-Induced Thrombocytopenia.
  Hematol Oncol Clin North Am. Aug 2007 21(4)
  589-607

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References

• Warkentin TE. Think of HIT. Hematology Am Soc
  Hematol Educ Program. 2006408-14
• Warkentin TE, Greinacher A et al. Treatment and
  Prevention of Heparin-Induced Thrombocytopenia.
  American College of Chest Physicians
  Evidence-Based Clinical Practice Guidelines(8th
  ed.). June 2008s340-s380

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Questions???