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Keywords:

  • HIT;
  • diagnosis;
  • treatment;
  • alternative anticoagulants;
  • monitoring

ABSTRACT

Clinical Development Phases I-III Regulatory, Quality, Manufacturing

Heparin-induced thrombocytopenia (HIT) without or with thrombosis (HIT-T) constitutes an acquired immune prothrombotic state, occurring in patients under unfractionated heparin or rarely low molecular weight heparin treatment. Heparin binding to secreted platelet factor-4 (PF4) generates PF4 neo-epitopes, against which polyclonal IgG-antibodies are produced. IgG-Hep/PF4 complexes bind on specific platelet, monocyte and endothelial cell Fcγ surface receptors, causing platelet consumption (thrombocytopenia), cell activation, release of prothrombotic tissue factor-bearing microparticles and thrombin generation. Mild to moderate thrombocytopenia and venous or arterial thrombosis are the two hallmarks of HIT. “4T” scoring-system predicts HIT-probability, while diagnosis is further confirmed via specific laboratory assays, which reveal either the presence of IgG antibodies against Hep/PF4 complex (immunological assays), or whether patient's serum can activate donor platelets in the presence of heparin (functional assays). HIT-treatment imposes immediate heparin cessation and initial parenteral anticoagulation with alternative anticoagulants, such as direct thrombin inhibitors (DTIs: lepirudin, argatroban, bivalirudin, desirudin) or indirect FXa inhibitors (IXaIs: danaparoid, fondaparinux). Monitoring of DTIs and IXaIs (via activated partial thromboplastin time or modern assays such as hemoclot thrombin inhibitor and anti-Xa activity, respectively) is essential especially in patients with renal or hepatic failure or in patients with HIT-related consumptive coagulopathy, in order to avoid serious bleeding events or anticoagulant underdosing. Vitamin K antagonists, which are contraindicated during acute phase, are permitted only after platelet count has substantially recovered and must be continued for at least 30 days and 3 months in isolated HIT and HIT-T, respectively, with target international normalized ratio (INR) between 2.0 and 3.0.