Aetiology

The aetiology of HIT is unknown. The rapid production of IgG antibodies (median of 4 days) without initial IgM antibody production suggests a secondary immune response, despite the absence of previous exposure to heparin in the majority of patients who develop HIT.[18][19] These observations have led to the hypothesis that sensitisation of the antiheparin/platelet factor 4 (PF4) antibody occurs as the result of other environmental exposures (e.g., bacterial infection) that produce the same antigen as the one produced by the heparin/PF4 complex.[20][21]

Pathophysiology

Platelet factor 4 (PF4) molecules bind to heparin on the surface of platelets to form a neo-antigen that is recognised by HIT (IgG) antibodies.[22][23] Antiheparin/PF4 antibodies bind to the large heparin/PF4 complexes and activate the same or adjacent platelets through their Fc receptors.[24][25] Activation of platelets leads to production of procoagulant platelet-derived microparticles and thrombin generation with the potential for development of the clinical manifestations that are characteristic of HIT (i.e., thrombocytopenia and venous and/or arterial thrombosis).[26][27] Activation of monocytes and the endothelium have also been implicated in the pathogenesis of HIT.[28][29][30] Typically, HIT antibodies are transient, becoming undetectable within 100 days (depending on the assay performed).[5][31]

Classification

Clinical classification of HIT

Isolated HIT:

  • Patients who have thrombocytopenia secondary to HIT antibodies without evidence of thrombosis or other sequelae of HIT.[4]

Delayed-onset HIT:

  • HIT that begins several days after heparin has been discontinued.[5]

Rapid-onset HIT:

  • Refers to a platelet count drop occurring within 24 hours of exposure to heparin due to persistence of HIT antibodies from a recent exposure to heparin (i.e., typically <30 days but can be up to 100 days).[5] An appropriate clinical picture and laboratory confirmation of HIT is essential because a rapid drop in platelet count is atypical for most patients with HIT and likely has other causes.

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