Coumadin-Induced Skin Necrosis
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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.
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
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
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.
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