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1 November 1997 | Volume 127 Issue 9 | Pages 804-812
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.
Author and Article Information
From McMaster University, Hamilton Health Sciences Corporation, and the Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada.
ARTICLE
The Pathogenesis of Venous Limb Gangrene Associated with Heparin-Induced Thrombocytopenia
Acknowledgments: The authors thank Dr. H. Alexander Heggtveit for his review of the pathologic material; Dr. Fred A. Ofosu for assays on some plasma samples; and Professor Robin S. Roberts and Jeremy N. Roberts for assistance with statistical analysis.
Grant Support: By the Heart and Stroke Foundation of Ontario (8-46924) and by the Hamilton Civic Hospitals Fund. Drs. Warkentin and Hayward are Research Scholars of the Heart and Stroke Foundation of Canada. Dr. Kelton is a Career Investigator for the Heart and Stroke Foundation of Ontario.
Requests for Reprints: Theodore E. Warkentin, MD, Department of Laboratory Medicine, Hamilton Health Sciences Corporation, Hamilton General Campus, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
Current Author Addresses: Drs. Warkentin and Elavathil: Department of Laboratory Medicine, Hamilton Health Sciences Corporation, Hamilton General Campus, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
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