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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
[+] Article and Author Information

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.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1997;127(9):804-812. doi:10.7326/0003-4819-127-9-199711010-00005
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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.

Figures

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Figure 1.
Gangrene of lower-limb digits in patient 1.

Necrosis occurred in eight toes.

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Figure 2.
Findings in patient 2.

A. Venous limb gangrene. B. An occluding thrombus can be seen in a subcutaneous venule (original magnification, x40). C. High-power view (original magnification, x100) of the subcutaneous venule from part B. D. The vein shows an occluding fibrin thrombus. The medium-sized muscular artery (bottom part of panel) is unremarkable. Hematoxylin and eosin staining was used for parts B, C, and D.

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Figure 3.
Thrombin-antithrombin complexes compared with protein C activity in patients with heparin-induced thrombocytopenia.Left.closed circlesRight.closed circles

Each data point represents thrombin-antithrombin complexes and protein C activity per single treatment day per patient; if multiple samples from one treatment day were available, the results were averaged. In both panels, open symbols represent three patients who developed venous limb gangrene, including patient 1 (◇), patient 3 (○), and patient 4 (square) (the latter developed severe venous limb ischemia). The diagonal line indicates an arbitrary ratio of thrombin-antithrombin complex to protein C of 40. Results obtained when heparin-induced thrombocytopenia was first diagnosed and before warfarin therapy began for two patients (open symbols) who developed venous limb gangrene or severe venous ischemia and for eight patients ( ) who subsequently received warfarin for deep venous thrombosis without developing venous limb gangrene. For comparison, results obtained when heparin-induced thrombocytopenia was diagnosed in 14 patients (closed squares) without clinically suspected deep venous thrombosis who did not subsequently receive warfarin are shown. Results in 16 patients who were receiving warfarin for heparin-induced thrombocytopenia, including 4 patients (open symbols) who developed venous limb gangrene or severe venous limb ischemia and 12 patients ( ), (9 of whom had deep venous thrombosis) who received warfarin without developing venous limb gangrene. More than one data point is shown for patients from whom plasma samples were available on more than 1 day of warfarin treatment.

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Figure 4.
Hemostatic markers in relation to clinical course in patient 3.

Venous limb gangrene and central skin necrosis occurred when warfarin was given during acute heparin-induced thrombocytopenia (first course of therapy, left). No adverse sequelae occurred when warfarin was given after thrombocytopenia resolved (second course of therapy, right).

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