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The Pathogenesis of Venous Limb Gangrene Associated with Heparin-Induced Thrombocytopenia
- Theodore E. Warkentin, MD;
- Leela J. Elavathil, MBBS;
- Catherine P.M. Hayward, MD;
- Marilyn A. Johnston, ART;
- Jean I. Russett, ART; and
- John G. Kelton, MD
- From McMaster University, Hamilton Health Sciences Corporation, and the Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada. 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.
Abstract
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.
- Copyright ©2004 by the American College of Physicians
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