Mechanism and Clinical Presentation of Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening complication of heparin anticoagulation, occurring in approximately 3% of patients treated with unfractionated heparin. Heparin and platelet factor 4 (PF4) are capable of forming multimolecular complexes. Given stoichiometric concentrations of heparin and platelet factor 4 (PF4), heparin may induce conformational changes in the PF4 molecule, rendering it antigenic. The subsequent immune response generates antibodies against heparin-PF4 complexes (HIT antibodies). Binding of these antibodies to FcγIIA receptors on the surface of platelets results in potent platelet activation. Binding of HIT antibodies to heparan sulfate-PF4 complexes on the surface of endothelial cells (ECs) causes EC activation with subsequent expression of tissue factor. Activation of platelets and of ECs together leads to marked thrombin generation, resulting in the hypercoagulable state in HIT. Clinically, HIT presents with two major sequelae: thrombocytopenia and thrombosis. Thrombocytopenia-that is, a platelet count below 150×10 ⁹ /L-is present in 85% - 90% of HIT patients and typically occurs between day 5 and day 10 of heparin treatment. The mean platelet count nadir is approximately 60×10 ⁹ /L. Alternatively, HIT may be associated with a marked fall in platelet count (≥50% of the initial value) whose nadir is not below 150×10 ⁹ /L. Despite the low platelet count, thrombosis rather than bleeding predominates. In HIT, the risk for thrombosis is 5% - 10% in the first 2 days; the 30-day cumulative risk is approximately 50%. Thromboses most often occur in deep veins of the lower limbs, frequently leading to pulmonary embolism. If thrombosis is severe or if it is detected in an unusual location in heparintreated patients, HIT should be suspected.