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Venous Limb Gangrene during Warfarin Treatment of Cancer-Associated Deep Venous Thrombosis

Theodore E. Warkentin, MD
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From McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Copyright ©2004 by the American College of Physicians

Acknowledgments: The author thanks Professor Jim Julian for assistance with statistical calculations, Drs. Jack Hirsh and Frederick A. Ofosu for helpful discussions, and Marilyn Johnston, Jo-Ann I. Sheppard, and Patti Simpson for performing the coagulation studies.

Grant Support: By the Heart and Stroke Foundation of Ontario (grant-in-aid #T-2967).

Requests for Single Reprints: Theodore E. Warkentin, MD, Hamilton General Hospital, Hamilton Health Sciences, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Ann Intern Med. 2001;135(8_Part_1):589-593. doi:10.7326/0003-4819-135-8_Part_1-200110160-00009
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Background: The cause of cancer-associated venous limb gangrene is unknown but could paradoxically be due to warfarin.

Objective: To determine the pathogenesis of venous gangrene in a patient with cancer.

Design: Case report.

Setting: University hospital in Ontario, Canada.

Patient: 66-year-old woman with metastatic lung cancer and deep venous thrombosis.

Measurements: Levels of vitamin K–dependent factors, additional coagulation factors, and thrombin–antithrombin complexes (marker of thrombin generation).

Results: During warfarin use, venous limb gangrene developed when the international normalized ratio (INR) reached 6.0 (therapeutic range, 2.0 to 3.0); at this time, the level of protein C (a vitamin K–dependent natural anticoagulant) was severely reduced, but thrombin–antithrombin complexes remained markedly elevated. The supratherapeutic INR was explained by the greatly reduced levels of factor VII, which correlated closely with protein C levels; therefore, the high INR was a surrogate marker for severely reduced protein C activity.

Conclusion: Warfarin may contribute to the pathogenesis of cancer-associated venous limb gangrene by leading to severe depletion of protein C while at the same time failing to reduce thrombin generation.


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Figure 1.
Venous limb gangrene complicating deep venous thrombosis (DVT) and cancer.Top.INRBottom.r2P3333333

Serial platelet counts and international normalized ratio ( ) values in relation to heparin and warfarin treatments. The abrupt increase in the INR and decrease in the platelet counts on discontinuation of heparin therapy are consistent with the increase in the consumption of coagulation factors and platelets in this patient with cancer-associated disseminated intravascular coagulation resistant to warfarin. Plasma factor studies. Eleven plasma samples obtained between days 10 and 18 of warfarin treatment were studied. Vitamin K, 5 mg intravenously, was given where indicated. Of the four coagulation factors that affect the INR (factors II, V, VII, and X), only factor VII levels explain the variability in the reciprocal of the INR: 1/INR= 0.178+0.974[factor VII level] ( = 0.883; < 0.001). Protein C activity showed a near-identity relationship with factor VII: [protein C level]= −0.01+0.94[factor VII level]. The following coagulation factor levels (not shown in the figure) were normal and are expressed as the mean (±SD) (normal range, 0.50 to 1.50×10 IU/L, except where noted): factor VIII, 2.87±1.37×10 IU/L; factor IX, 0.81±0.34×10 IU/L; factor XI, 0.69±0.12×10 IU/L; factor XII, 0.54±0.09×10 IU/L; free protein S, 125±18 nmol/L (normal range, 86 to 221 nmol/L); fibrinogen, 2.67±0.55 g/L (normal range, 1.5 to 4 g/L); and antithrombin activity, 1.03±0.06×10 IU/L (normal range, 0.77 to 1.30×10 IU/L).

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Figure 2.
Pathogenesis of warfarin-associated venous limb gangrene complicating heparin-induced thrombocytopenia or cancer.INR

The pathogenesis of warfarin-associated venous limb gangrene is shown in relation to its typical clinical triad—supratherapeutic international normalized ratio ( ), microvascular thrombosis, and thrombocytopenia. The central paradox is persisting formation of thrombin despite markedly depleted plasma factor VII level, which is paralleled by severely depleted protein C activity, leading to impaired downregulation of thrombin generation in the microvasculature and, consequently, microvascular thrombosis.

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Summary for Patients

Gangrene of the Leg during Warfarin Treatment in a Patient with Cancer

Copyright ©2004 by the American College of Physicians


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