THE PATHOGENESIS OF VENOUS LIMB GANGRENE ASSOCIATED WITH HEPARIN-INDUCED THROMBOCYTOPENIA

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 dee p venous thrombosis (venous limb gangrene) sometimes associated with h eparin-induced thrombocytopenia has not been well characterized. Objec tive: To study the pathogenesis of venous limb gangrene associated wit h heparin-induced thrombocytopenia. Design: Characterization (based on descriptive and case-control studies) of a novel syndrome of limb los s and hypothesis testing by analysis of plasma samples. Setting: Five university-associated hospitals in one medical community. Patients: Cl inical and laboratory records of 158 patients with heparin-induced thr ombocytopenia were reviewed to identify patients with venous limb gang rene (n = 8), limb arterial thrombosis (n = 10), and uncomplicated dee p venous thrombosis (n = 58). Measurements: Clinical and laboratory fa ctors associated with venous limb gangrene, including thrombin-antithr ombin complexes and vitamin K-dependent procoagulant and anticoagulant factors. Results: Warfarin treatment was more frequently associated w ith venous limb gangrene than with limb arterial thrombosis (8 of 8 pa tients compared with 3 of 10 patients; P = 0.004). The anticoagulant e ffect of warfarin seemed greater in the 8 patients with venous limb ga ngrene than in the 58 patients who did not develop gangrene (median in ternational normalized ratio, 5.8 compared with 3.1; P < 0.001). Compa red with plasma from controls, plasma from patients with venous limb g angrene 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. Conclus ions: Warfarin treatment of deep venous thrombosis associated with hep arin-induced thrombocytopenia is a possible cause of venous limb gangr ene, perhaps because of acquired failure of the protein C anticoagulan t pathway to regulate thrombin generation.