The peculiar pathogenesis of heparin-induced thrombocytopenia (HIT), involving a "self" antigen-platelet factor 4 (PF4) bound to heparin-and resulting antibody-mediated platelet activation, is a model for thrombosis triggered by drug-induced autoimmunity. The high probability of forming an immune response to heparin, and the highly-variable clinical significance of a positive laboratory test-depending on the type of assay and the magnitude of a given positive test result-provides lessons regarding appropriate interpretation of diagnostic laboratory testing in the context of pretest probability. The relatively high risk of inducing microvascular thrombosis due to coumarin-induced vitamin K antagonism attests to the dangers of a compromised protein C natural anticoagulant system in the setting of a hypercoagulability state such as HIT. Unusual immunologic features of HIT, such as the dissociation between immunogenicity (induction of immune response) and cross-reactivity (capacity to form the antigens recognized by HIT antibodies)of the implicated polysaccharide anticoagulants, and the generally rapid formation and disappearance of anti-PF4/heparin antibodies, suggest that further lessons regarding HIT immunopathogenesis remain to be learned.