Coumadin-Induced Skin Necrosis

Author(s): 
Janice M. Beitz, PhD, RN, CS, CNOR, CWOCN

Introduction

Coumadin-induced skin necrosis (CISN) is a rare, unusual, and unpredictable integumentary complication of anticoagulant therapy. Also known as warfarin-induced skin necrosis (WISN), the dermatologic complication occurs in 0.01 to 0.1 percent of warfarin-treated patients. As anticoagulation is a component of therapy for many major chronic illnesses, recognition of the condition is crucial for prompt intervention in clinical practice. The syndrome also can result in substantial morbidity and possible fatality. This article addresses the historical background, pathogenesis, clinical presentation, and prevention/treatment issues associated with CISN.

Historical Background

Coumadin (Bristol-Myers Squibb, New York, NY) was first introduced in 1941. Warfarin-induced skin necrosis was described by Flood and colleagues1 who reported a case of a gangrenous breast but erroneously believed it was due to an underlying coagulopathy and not the drug therapy.2,3 In 1954, Verhagen described a series of 13 patients on dicumarol who developed necrosis, but he incorrectly suggested the necrosis was associated with the underlying disease being treated when in fact it was complicated by a thrombosis and dicumarol therapy.4 Kipen first correctly ascribed the gangrenous skin changes to anticoagulant therapy.5

CISN is known by several names: WISN, coumarin-congener-associated skin necrosis, and warfarin dermal gangrene. Important to note is that coumarin is the parent compound for several anticoagulants (i.e., sodium warfarin [Coumadin], bishydroxycoumarin [dicoumarol]). Coumarin itself is not an anticoagulant; therefore, calling the condition by that name is somewhat of a misnomer.6

Clinical Presentation

A constellation of typical historical and clinical features is often described in CISN case reports (Table 1). The prototypical patient is an obese, middle-aged, perimenopausal woman being treated for deep vein thrombosis, pulmonary embolism, and cerebrovascular or coronary thrombosis. Classically, the lesions appear in the breast, buttock, abdomen, or thigh where significant underlying subcutaneous fat tissue is present. The condition is most often unilateral, but 30 percent of cases occur bilaterally with multiple lesions. Onset of skin changes may begin from day one to day ten, with a peak incidence on days three to six after initiating Coumadin.2,6,7 However, case reports indicate CISN occurs much later than the "typical" time of onset.8 One suggestion for the late-onset phenomenon is lack of drug compliance with patients forgetting, or purposely choosing to omit, the drug on some days.

CISN has affected persons ranging in age from 16 to 93 (median: 54) years.9 Although the condition also occurs in men, the female:male ratio is described as 9:1. When CISN affects males, the breast is rarely involved, but the penis may be a site of necrosis.10-12

A classic pattern of skin changes occurs when the condition commences. Patients complain of paresthesias, sensations of pressure, and extreme pain. Areas of erythematous flush may become edematous and have a peau d'orange effect. Within 24 to 48 hours, petechiae develop that progress to hemorrhagic bullae and change quickly to full-blown necrotic eschar. The eschar may eventually slough or require extensive surgical debridement.11,12

Etiology/Pathophysiology

Little is known regarding the exact historical changes that activate the pathology because biopsies are usually done later in the necrotic-generating event. However, scrutiny of patient histories has identified associated risk factors. These include the "classic" patient characteristics described previously, large loading doses of Coumadin, and acute thrombosis conditions.10,12,13

Several theories have been suggested related to the pathogenesis of CISN, although the exact etiology is obscure.

References: 

1. Flood EP, Redish MH, Bociek S, et al. Thrombophlebitis migrans disseminata: Report of a case in which gangrene of breast occurred. NY State J Med 1943;43:1121-4.
2. Berkompas DC. Coumadin skin necrosis in a patient with a free Protein S deficiency: Case report and literature review. India Med 1991;84(11):788-91.
3. Hiers CL. Case presentation of Coumadin-induced skin necrosis. J Arkansas Med Soc 1993;89(9):443-4.
4. Verhagen H. Local hemorrhage and necrosis of skin and underlying tissues during anticoagulant therapy with dicumarol or dicumacyl. Acta Medica Scandinavica 1954;148:453.
5. Kipen CS. Gangrene of the breast: A complication of anticoagulant therapy. N Engl J Med 1961;265:638-40.
6. Brooks LW, Blais FX. Coumadin-induced skin necrosis. J Am Osteopath Assoc 1991;91(6):601-5.
7. Eby CS. Warfarin-induced skin necrosis. Hematol Oncol Clin North Am 1993;7(6):1291-300.
8. Essex DW, Wynn SS, Jin DK. Late onset warfarin-induced skin necrosis: Case report and review of the literature. Am J Hematol 1998;57:233-7.
9. Gelwix TJ, Beeson MS. Warfarin-induced skin necrosis. Am J Emerg Med 1998;16(5):541-3.
10. Ad-El D, Meirovitz A, Weinberg A, et al. Warfarin skin necrosis: Local and systemic factors. Br J Plast Surg 2000;53:624-6.
11. Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg 2000;87:266-72.
12. De Franzo AJ, Marasco P, Argenta LC. Warfarin-induced necrosis of the skin. Ann Plast Surg 1995;34:203-8.
13. Ng T, Tillyer ML. Warfarin-induced skin necrosis associated with Factor V Leiden and Protein S deficiency. Clin Lab Haematol 2001;23:261-4.
14. Nalbadian RM, Masler IJ, Barrett JL, et al. Petechiae, ecchymoses, and necrosis of skin induced by Coumadin congeners. JAMA 1965;192:603.
15. Haimovici H, Bergan JJ. Coumadin-induced skin necrosis versus venous gangrene of the extremities. J Vasc Surg 1987;5(4):655-6.
16. Brigden ML. The hypercoagulable state: Who, how, and when to test and treat. Postgrad Med 1997;101(5):249-63.
17. McKnight JT, Maxwell AJ, Anderson RL. Warfarin necrosis. Arch Fam Med 1992;1:105-8.
18. Slutzki S, Bogokowsky H, Gilboa Y, Halpern Z. Coumadin-induced skin necrosis. Int J Dermatol 1984;23:117-9.
19. Gailani D, Reese EP. Anticoagulant-induced skin necrosis in a patient with hereditary deficiency of Protein S. Am J Hematol 1999;60:231-6.
20. Martin FL. Warfarin-induced necrosis. Am J Nurs 1999;99(8):53-4.
21. Comp PC, Elrod JP, Karzenski S. Warfarin-induced skin necrosis. Semin Thromb Hemost 1990;16(4):293-8.
22. Harviel JD. Recurrent Coumadin-induced soft tissue necrosis resulting in mastectomy. Milit Med 1993;158:283-4.
23. Viegas GV. Coumadin skin necrosis: Pedal manifestations. J Am Podiatr Med Assoc 1992;82(9):463-8.
24. Timmons J. Dressing selection for the treatment of coumarin necrosis. Nurs Stand 2000;14(49):66-8, 70.
25. Cheng A, Scheinfeld NS, McDowell B, Dokras A. Warfarin skin necrosis in a postpartum woman with Protein S deficiency. Obstet Gynecol 1997;90(4):671-2.
26. Miura Y, Ardenghy M, Ramasastry S, et al. Coumadin necrosis of the skin: Report of four patients. Ann Plast Surg 1996;37:332-7.
27. Jillella AP, Lutcher CL. Reinstituting warfarin in patients who develop warfarin skin necrosis. Am J Hematol 1996;52:117-9.

Additional Reading

1. Bal BS, Gurba DM. Coumadin-induced necrosis of the skin after total knee replacement. J Bone Joint Surg 1991;73-A(1):129-30.
2. Colman RW, Rao AK, Rubin RN. Warfarin skin necrosis in a 33-year old woman. Am J Hematol 1993;43:300-3.
3. Gibbar-Clements T, Shirrel D, Dooley R, Smiley B. The challenge of warfarin therapy. Am J Nurs 2000;100(3):38-40.
4. Hirsh J. Use of warfarin (coumarin). Heart Dis Stroke 1993;2:209-16.
5. Hirsh J, Dalen J, Anderson D, et al. Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:8S-21S.
6. Humphries JE, Gardner JH, Connelly JE. Warfarin skin necrosis: Recurrence in the absence of anticoagulant therapy. Am J Hematol 1991;37:197-200.
7. Locht H, Lindstrom FD. Severe skin necrosis following warfarin therapy in a patient with Protein C deficiency. J Inter Med 1993;233:287-9.
8. Merrill JT, Lahita RG. Avoiding the serious consequences of antiphospholipid syndrome. J Musculoskel Med 1995;12(9):43-53.
9. Shetty H, Woods F, Routledge PA. The pharmacology of oral anticoagulants: Implications for therapy. J Heart Valve Dis 1993;2:53-62.
10. Sternberg ML, Pettyjohn FS. Warfarin sodium-induced necrosis. Ann Emerg Med 1995;26:94-7.
11. Stewart AJ, Penman ID, Cook MK, Ludlam CA. Warfarin-induced skin necrosis. Postgrad Med J 1998;75(882):233-5.
12. Zimbelman J, Lefkowitz J, Schaeffer C, et al. Unusual complications of warfarin therapy: Skin necrosis and priapism. J Pediatr 2000;137(2):266-8.



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