Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction that results when pathogenic immunoglobulin (Ig)G antibodies are formed that recognize neoepitopes on a “self” protein – platelet factor 4 (PF4) – after PF4 has formed complexes with heparin (1). Multimolecular complexes of heparin, PF4, and IgG form on platelet surfaces (2).Occupancy of the platelet Fcγ IIa receptors by the resulting immune complexes induces platelet activation, with concomitant activation of coagulation (3), perhaps via the generation of procoagulant platelet microparticles (MPs). Once triggered, the prothrombotic risk persists for a time, even after stopping heparin. This scheme of pathogenesis is fundamentally unique.

Unlike HIT, other immune-mediated thrombocytopenic disorders are caused by antibodies that recognize one or more platelet surface glycoproteins. The Fc moieties of the platelet-bound antibodies are recognized by Fc receptors of the mononuclear phagocytic system; this results in the clearance (not activation) of the antibody-coated platelets and often produces severe thrombocytopenia and mucocutaneous bleeding. This is also the mechanism of all other (non-HIT) drug-induced immune thrombocytopenias, except that the antibodies bind to a drug (or drug metabolite)/glycoprotein complex.

The clinical importance of HIT derives from its high frequency (3–5%) in certain patient populations, particularly postoperative patients receiving unfractionated heparin (UFH) antithrombotic prophylaxis for 1 to 2 weeks, and because of its paradoxical strong association with thrombosis (odds ratio, 20–40) (1). The frequency of HIT is less with low-molecular-weight heparin (LMWH), compared with UFH. Venous thrombosis predominates, despite HIT being a primary platelet activation disorder. Understanding the pathophysiological basis of venous thrombosis predominance in HIT might help unravel the role that platelets play in contributing to venous thrombosis.