Laboratory Evaluation of Heparin‐Induced Thrombocytopenia

Heparin‐induced thrombocytopenia (HIT) is a prothrombotic disorder caused by platelet‐activating IgG antibodies that recognize platelet factor 4 (PF4) heparin complexes. Laboratory detection of such “HIT antibodies” is required for definitive diagnosis. Laboratory tests for HIT can be broadly classified into: (a) platelet activation (or functional) assays; and (b) PF4‐dependent antigen assays (immunoassays). An important diagnostic problem is that heparin administration results in frequent generation of anti‐PF4 heparin antibodies, yet only a small minority of antibody‐positive patients develops clinically evident HIT; such patients usually have strong positive test results. Non‐HIT thrombocytopenia occurs commonly in hospitalized patients, causing considerable “over‐diagnosis” of HIT if any positive test—irrespective of its strength or clinical context—is assumed automatically to indicate a diagnosis of HIT. According to the “iceberg model” of HIT, among the many antibody‐positive patients, those with clinical HIT are found in the subset (“tip of the iceberg”) testing positive for platelet‐activating anti‐PF4 heparin antibodies. Platelet activation tests that use “washed” platelets are the most useful, as they combine high diagnostic sensitivity with greater specificity for HIT than the PF4‐dependent immunoassays. In turn, IgG‐specific assays have greater diagnostic specificity than polyspecific immunoassays that additionally detect (non‐pathogenic) IgA and IgM class antibodies; this is because pathogenic PF4 heparin IgG complexes activate platelets through platelet Fc?IIa (IgG) receptors. Although commercial enzyme immunoassays are the most widely performed assays to diagnose HIT, there is increasing recent interest in “rapid” assays, including particle‐based immunoassays and lateral‐flow immunoassays.