Heparin-Induced Thrombocytopenia: Pathophysiology, Diagnosis, and Treatment 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.