Article
Pharmacotherapy of heparin-induced thrombocytopenia: Therapeutic options and challenges in the clinical practices

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Highlights

  • Heparin-induced thrombocytopenia (HIT) is an immune response results from exposure to heparin or low-molecular weight heparin (LMWH).

  • Early diagnosis based on clinical evaluation improves clinical outcomes.

  • Once HIT is suspected, all heparin forms and LMWH must be discontinued.

  • Nonheparin anticoagulant should be considered to prevent HIT complications.

Heparin-induced thrombocytopenia (HIT) is an immune response to heparin associated with significant morbidity and mortality in hospitalized patients if unidentified as soon as possible, owing to thromboembolic complications involving both arterial and venous systems. Early diagnoses based on a comprehensive interpretation of clinical and laboratory information improves clinical outcomes. Management principles of strongly suspected HIT should not be delayed for laboratory result confirmation. Treatment strategies have been introduced including new, safe, and effective agents. This review summarizes the clinical therapeutic options for HIT addressing the use of parenteral direct thrombin inhibitors and indirect factor Xa inhibitors as well as the potential non-vitamin K antagonist oral anticoagulants.

Section snippets

Risk factors

Patients' exposure to heparin is the main risk factor and a critical step in the development of HIT (Table 1). A heparin source such as bovine lung is more immunogenic than those produced from porcine intestine,15 and the risk of HIT rises with the length and volume of exposure to heparin as well as the route of administration,16 and more likely with intravenous heparin than subcutaneous administration.17, 18, 19 Nevertheless, HIT can develop from any heparin exposure, including incidental

Pathophysiology

HIT is an autoimmune response caused by the formation of antibodies that activate platelets after heparin administration.27, 28 This response leads to an interaction with PF4, which is normally found on endothelial cells and platelets, and formation of immunogenic heparin–PF4 complexes that cause an immunologic response. Antibodies are generated resulting in a complex forming among antibodies, heparin, and PF4. This complex leads to further platelet activation, resulting in formation of

Clinical presentation and laboratory diagnosis

HIT may occur rapidly or with a delayed onset, depending on the presence of heparin–PF4 antibodies from a previous administration and sensitization of heparin and related molecules may induce rapid-onset HIT.33 In patients exposed to heparin for the first time, the onset of HIT may occurs 5–10 days after receiving heparin.4, 5, 12, 34 The thrombocytopenia in HIT is usually moderate in severity, with a median platelet count being between 50 and 80 × 109/L, although the nadir platelet count can

Renal replacement therapy

Renal replacement therapy is a term used to cover a large number of different procedures patients with renal failure such as hemodialysis procedures. The most commonly used anticoagulant in this setting is heparin to maintain the patency during these procedures. Argatroban and danaparoid have both been used and are recommended for patients with HIT who need renal replacement therapy74, 75, 76; the use of regional citrate is suggested for patients with a past history of HIT.4, 5

Pregnancy

Pregnant patients have a lower risk of developing HIT during pregnancy than in nonpregnant populations, especially when LMWH is used.77, 78 Nonheparin anticoagulants should be initiated once HIT is confirmed and heparin should be immediately discontinued. The evidence available on the efficacy and safety of nonheparin anticoagulants in this patient population is still very low. For pregnant women with acute or subacute HIT, danaparoid has been suggested and the use of lepirudin or fondaparinux

Switching to an oral anticoagulant

The risk for severe thrombotic complication of the microvasculature is associated with acute HIT. Avoidance of vitamin K antagonists (VKA) such as warfarin (which can induce skin necrosis owing to rapid depletion of protein C, a natural occurring anticoagulant) and variations in half-lives of vitamin K–dependent factors should be considered.79 Once HIT is confirmed, patient receiving VKA should be held and International Normalized Ratio (INR) should be reversed by vitamin K. Platelet recovery

Duration of anticoagulation for HIT

The risk of HIT for subsequent venous thromboembolism is reversible and transient. Therefore, anticoagulation duration is suggested to be continued for 4–6 weeks in patients with confirmed isolated HIT and for a minimum of 12 weeks in patients associated with thromboembolic events.4, 5, 81

Platelet administration

Because thromboembolic events are seen as complications for HIT more than bleeding diathesis and owing to the clinical concern that platelet administration may increase the risk of thromboembolic events, platelet administration is unnecessry.4, 5, 12

Conclusions and clinical considerations

The diagnosis of HIT requires clinical evaluation and laboratory confirmation. Platelet count monitoring should performed every 2 or 3 days in patient population with a risk of HIT >1%. When HIT is strongly suspected, management should include immediate discontinuation of all heparin formulations and the start of alternative, nonheparin anticoagulants. VKA should not be given. Instead, if VKA was given, reverse elevated INR by administering vitamin K and avoid platelet transfusions. A serotonin

References (81)

  • J.G. Kelton

    Heparin-induced thrombocytopenia: an overview

    Blood Rev

    (2002)
  • D. Sheridan et al.

    A diagnostic test for heparin-induced thrombocytopenia

    Blood

    (1986)
  • J.I. Zwicker et al.

    Thrombosis and ELISA optical dentistry values in hospitalized patients with heparin-induced thrombocytopenia

    J Thromb Haemost

    (2004)
  • B.H. Chong

    Heparin-induced thrombocytopenia

    J Thromb Haemost

    (2003)
  • G.K. Lo et al.

    Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings

    J Thromb Haemost

    (2006)
  • A. Cuker et al.

    Predictive value of the 4T’s scoring system for the heparin-induced thrombocytopenia: a systematic review and meta-analysis

    Blood

    (2012)
  • D.E. Wallis et al.

    Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia

    Am J Med

    (1999)
  • R.L. Levine et al.

    Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction

    Chest

    (2006)
  • N. Lubenow et al.

    Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies

    Blood

    (2004)
  • B.H. Chong et al.

    Heparin-induced thrombocytopenia: studies with a new low molecular weight heparinoid, Org 10172

    Blood

    (1989)
  • D.A. Garcia et al.

    Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

    Chest

    (2012)
  • K. Krauel et al.

    Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfate heparin, with platelet factor 4 and anti/PF4/heparin antibodies

    Blood

    (2012)
  • T.E. Warkentin

    HIT: treatment easier, prevention harder

    Blood

    (2012)
  • F.J. Anniccherico et al.

    Dabigatran for heparin-induced thrombocytopenia

    Mayo Clin Proc

    (2013)
  • M. Sharifi et al.

    Treatment of heparin induced thrombocytopenia with oral anticoagulants

    J Am Coll Cardiol

    (2014)
  • A. Davenport

    Antibodies to heparin-platelet factor 4 complex: pathogenesis, epidemiology, and management of heparin-induced thrombocytopenia in hemodialysis

    Am J Kidney Dis

    (2009)
  • H.N. Magnani

    A review of 122 published outcomes of danaparoid anticoagulation for intermittent haemodialysis

    Thromb Res

    (2010)
  • I.A. Greer et al.

    Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy

    Blood

    (2005)
  • T.E. Warkentin et al.

    A 14-year study of heparin-induced thrombocytopenia

    Am J Med

    (1996)
  • T.E. Warketin

    Heparin-induced thrombocytopenia: pathogenesis and management

    Br J Haematol

    (2003)
  • T.E. Warketin

    Heparin-induced thrombocytopenia. Diagnosis and Management

    Circulation

    (2004)
  • D.B. Cines et al.

    Congenital and acquired thrombocytopenia

    Hematology Am Soc Hematol Educ Program

    (2004)
  • H. Watson et al.

    Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition

    Br J Haematol

    (2012)
  • T.E. Warketin

    An overview of the heparin-induced thrombocytopenia syndrome

    Semin Thromb Hemost

    (2004)
  • M. Franchini

    Heparin induced thrombocytopenia: an update

    Thrombosis J

    (2005)
  • L. Rice

    Heparin-induced thrombocytopenia: myths and misconceptions

    Arch Intern Med

    (2004)
  • A. Greinacher et al.

    Heparin-associated thrombocytopenia: isolation of the antibody and characterization as the major antigen

    Thromb Haemost

    (1994)
  • J. Amiral et al.

    Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia

    Thromb Haemost

    (1992)
  • V.R. Bhatt et al.

    Nonheparin anticoagulants for heparin-induced thrombocytopenia

    N Engl J Med

    (2013)
  • S. Nand et al.

    Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated as a single institution

    Am J Hematol

    (1997)
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