- BACKGROUND: Platelet-mediated arterial occlusion is a well-recognized cause of limb loss in patients with heparin-induced thrombocytopenia. However, the syndrome of distal ischemic necrosis complicating the deep venous thrombosis (venous limb gangrene) sometimes associated with heparin-induced thrombocytopenia has not been well characterized. OBJECTIVE: To study the pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. DESIGN: Characterization (based on descriptive and case-control studies) of a novel syndrome of limb loss and hypothesis testing by analysis of plasma samples. SETTING: Five university-associated hospitals in one medical community. PATIENTS: Clinical and laboratory records of 158 patients with heparin-induced thrombocytopenia were reviewed to identify patients with venous limb gangrene (n = 8), limb arterial thrombosis (n = 10), and uncomplicated deep venous thrombosis (n = 58). MEASUREMENTS: Clinical and laboratory factors associated with venous limb gangrene, including thrombin-antithrombin complexes and vitamin K-dependent procoagulant and anticoagulant factors. RESULTS: Warfarin treatment was more frequently associated with venous limb gangrene than with limb arterial thrombosis (8 of 8 patients compared with 3 of 10 patients; P = 0.004). The anticoagulant effect of warfarin seemed greater in the 8 patients with venous limb gangrene than in the 58 patients who did not develop gangrene (median International normalized ratio, 5.8 compared with 3.1; P < 0.001). Compared with plasma from controls, plasma from patients with venous limb gangrene had a higher ratio of thrombin-antithrombin complex to protein C activity during warfarin treatment. No hereditable abnormalities of the protein C anticoagulant pathway were seen in any patient. CONCLUSIONS: Warfarin treatment of deep venous thrombosis associated with heparin-induced thrombocytopenia is a possible cause of venous limb gangrene, perhaps because of acquired failure of the protein C anticoagulant pathway to regulate thrombin generation.