title: HITlights: a career perspective on heparin-induced thrombocytopenia.
abstract: Two decades of research into heparin-induced thrombocytopenia (HIT) permit a personal historical perspective on this fascinating syndrome. Previously, the frequency of HIT was unknown, although complicating thrombosis was believed to be rare and primarily arterial. The opportunity to apply a remarkable test for "HIT antibodies"--the (14) C-serotonin-release assay (SRA)--to serial plasma samples obtained during a clinical trial of heparin thromboprophylaxis, provided insights into the peculiar nature of HIT, such as, its prothrombotic nature--including its strong association with venous thrombosis (RR = 11.6 [95%CI, 6.4-20.8; P < 0.0001); its more frequent occurrence with unfractionated versus low-molecular-weight heparin; the "iceberg" model, which states that among the many patients who form anti-PF4/heparin antibodies during heparin therapy, only a minority whose antibodies evince strong platelet-activating properties develop HIT; and the characteristic HIT timeline, whereby serum/plasma antibodies are readily detectable at or prior to the HIT-associated platelet count fall. Applying the SRA also to patients encountered in clinical practice led to recognition of warfarin-induced venous limb gangrene (for which HIT is a major risk factor via its extreme hypercoagulability) and delayed-onset HIT (whereby thrombocytopenia begins or worsens following heparin discontinuation, due to the ability of HIT antibodies strongly to activate platelets even in the absence of heparin--so-called heparin-"independent" platelet activation). Recent concepts include the increasing recognition of HIT "overdiagnosis" (due to the low diagnostic specificity of the widely-applied PF4-dependent immunoassays), and the observation that HIT-associated consumptive coagulopathy is a risk factor for treatment failure with PTT-adjusted direct thrombin inhibitor therapy ("PTT confounding" secondary to HIT-associated coagulopathy).
authors.affiliation: Department of Pathology and Molecular Medicine, Michael G DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. twarken@mcmaster.ca
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Warkentin
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D006493:Heparin / Q000009:adverse effects* / Q000627:therapeutic use; D015539:Platelet Activation / Q000187:drug effects / Q000276:immunology; D010976:Platelet Count; D010978:Platelet Factor 4 / Q000097:blood / Q000276:immunology; D012701:Serotonin / Q000097:blood / Q000276:immunology; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000276:immunology / Q000628:therapy; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy / Q000276:immunology
chemical_list: D000925:Anticoagulants; D001323:Autoantibodies; D012701:Serotonin; D010978:Platelet Factor 4; D006493:Heparin