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Warfarin-induced Skin Necrosis

Coumadin-Induced Skin Necrosis

Warfarin-induced skin necrosis is a rare but possibly life-threatening complication of warfarin treatment and is predominantly seen in patients with underlying coagulation factor deficiencies. A sudden onset of edema, petechiae and subsequent necrosis of the skin within several days after administering warfarin is the typical clinical presentation. In the absence of specific laboratory tests, clinical criteria and identifying recent warfarin use during history taking are key steps to make the diagnosis.


Warfarin is an anticoagulant drug used for treatment and prophylaxis of various hypercoagulable disorders, but several complications may arise, one of them being skin necrosis, as warfarin can paradoxically induce a hypercoagulable state [1] [2] [3]. Although warfarin-induced skin necrosis (WISN) develops in 0.01%-0.1% (approximately 1 in 10,000) of patients who receive warfarin, its appearance must be recognized early on [3] [4] [5] [6]. Several risk factors have been established, including deficiencies of several coagulation factors (factor V Leiden, antithrombin III, proteins C and S), concomitant presence of antiphospholipid syndrome, hyperhomocysteinemia, but also obesity and female gender, with a female-to-male ratio of 4:1 [1] [4] [5]. Moreover, aggressive use of warfarin without prior administration of heparin is another well-documented risk factor [4] [5] [7]. The clinical presentation is distinguished by a sudden onset of erythematous macules, ecchymoses and purpuric lesions 3-10 days after initiation of warfarin use while accompanying edema and paresthesia is frequent [2] [5] [7]. The most common sites are the penis in males and breasts in females, whereas the buttocks, thighs, and limbs (especially calves) are observed as common locations in both genders [1] [4]. If the diagnosis is delayed, the progression of lesions to hemorrhagic bullae, ulcers and full-thickness necrosis can ensue, which may significantly increase the risk for further complications [5] [7].

Severe Pain
  • Three days after discharge, she was readmitted after complaining of severe pain and swelling of the fatty tissue of her right flank that began the day after she was discharged. Some blistering and necrosis were noted on the lesion.[ncbi.nlm.nih.gov]
  • Our patient is a 52 year old Egyptian female with PMH of diabetes and hypertension with a history of a cerebrovascular accident 2 months ago with residual aphasia and bulbar symptoms.[slideshare.net]
  • […] 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[woundsresearch.com]


The diagnosis of WISN must be made as early as possible, as its early recognition could be lifesaving [3]. Because no conclusive laboratory tests exist to confirm WISN, the diagnosis relies on the ability of the physician to reveal recent warfarin use and detect characteristic lesions of the skin [4] [5] [6] [7]. For this reason, the first, and probably the most important step during the diagnostic workup, is a detailed patient history that will identify recent administration of warfarin, but also if patients suffer from any of the mentioned disorders that could predispose them to WISN, including deep vein thrombosis (DVT) and pulmonary embolism (PE), both being recognized as predisposing conditions for WISN [4] [5]. Furthermore, a complete physical examination of the skin will confirm the presence of purpuric, hemorrhagic and necrotic lesions in common areas, in which case immediate clinical suspicion toward warfarin should be raised. A complete coagulation panel should be performed, but findings can often be normal. However, a biopsy with histological examination could be of benefit [5] [6]. Full-thickness necrosis of the epidermis and both dermal and subcutaneous venous thrombosis are characteristic features of WISN, as are extravasated erythrocytes, endothelial cell damage, and fibrin deposits in superficial dermal vessels and in postcapillary venules [5] [6].

Muscle Calcification
  • Later, an incisional skin biopsy was performed, and the pathology showed extensive cutaneous necrosis with associated neutrophilic inflammation, without smooth muscle calcification consistent with the clinical impression of WISN ( Figures 4 and 5 ).[omicsonline.org]


  • After a consultation with a hematologist, treatment with protein C concentrate (human) was initiated. Within 24 hours of treatment with this product, progression of necrosis stopped, and the patient's respiratory failure resolved.[ncbi.nlm.nih.gov]
  • A patient with a history of deep vein thrombosis presented with painful bruising and blistering on his left leg 7-10 days after warfarin treatment.[ncbi.nlm.nih.gov]
  • Early recognition of this syndrome has important implications in the treatment of such patients and may reduce the severity of complications.[ncbi.nlm.nih.gov]
  • A 55-year-old woman presented with an extensive warfarin-induced skin necrosis while an inpatient for treatment of a pulmonary embolism and thromboembolic stroke. She had a background of diabetes mellitus, hypertension and dyslipidaemia.[ncbi.nlm.nih.gov]
  • Warfarin-induced skin necrosis is a rare but possibly life-threatening complication of warfarin treatment and is predominantly seen in patients with underlying coagulation factor deficiencies.[symptoma.com]


  • […] subcutaneous capillaries, venules, and deep veins Endothelial cell damage resulting in ischemic skin necrosis and marked RBC extravasation No vascular inflammation and arterial involvement 9 10 11 Management Early diagnosis and drug withdrawal improve prognosis[slideplayer.com]
  • Titrating warfarin doses over an extended period promotes a more gradual decline in the protein C level, similar to that of the other longer-lived vitamin K–dependent coagulant factors. 7 Prompt diagnosis of warfarin-induced skin necrosis is crucial for prognosis[pharmacytimes.com]
  • The prognosis is often poor with a mortality rate of 60-80%, often from sepsis [ 7 ].[omicsonline.org]
  • As the prognosis of CUA is worse with more than 80% mortality with severe CUA, early diagnosis and initiation of treatment plays a key role. The most common differential diagnosis of CUA is WISN especially, when patient is on warfarin.[pubs.sciepub.com]
  • Protein C deficiency does NOT appear to cause arterial thrombosis. [ 5 ] Prognosis There is a 10- to 15-fold risk of VTE. [ 5 ] However, there is a marked variation in risk among families with protein C deficiency, that cannot be explained by the genetic[patient.info]


  • Warfarin-induced skin necrosis (WISN) is a disorder of unclear etiology that predominantly affects obese women.[ncbi.nlm.nih.gov]
  • The etiology of warfarin-induced skin necrosis has not been definitively established.[ncbi.nlm.nih.gov]
  • 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[woundsresearch.com]
  • However, if antibodies are present they are a marker for HIT. 2, 4, 5 Only 10% to 20% of patients who develop HIT antibodies during subcutaneous administration of UFH or LMWH will develop skin lesions. 2 ETIOLOGY AND PATHOPHYSIOLOGY Generally develops[mhmedical.com]
  • […] replacement therapy with fresh frozen plasma is started Homozygous protein C deficiency can be cured with liver transplant; however, this is usually too risky so replacement is preferred treatment Must exclude acquired causes of protein C deficiency Etiology[pathologyoutlines.com]


  • Management of Acute Hemorrhage Platelets Plasma and Specialized Coagulation Concentrate New Approaches for the Therapy of Bleeding Disorders Overview of Venous Thromboembolism Thrombophilia Genetics Epidemiology and Risk Factors for Venous Clinical Manifestations[books.google.com]
  • Epidemiology It is estimated that in a Caucasian population, protein C deficiency is found in 2-5% of patients with venous thromboembolism (VTE), in 5-10% of those with recurrent VTE and in 0.2-0.5% of the general population. [ 4 ] However, genetic predisposition[patient.info]
  • Drug-induced skin pigmentation: epidemiology, diagnosis and treatment. Am J Clin Dermatol. 2001;2:253-262. To comment on this article, contact rdavidson@uspharmacist.com.[uspharmacist.com]
Sex distribution
Age distribution


  • This article reviews the pathophysiology and clinical features of warfarin-induced skin necrosis.[ncbi.nlm.nih.gov]
  • In this article the historical, clinical, and pathophysiologic features of this hypercoagulable event are reviewed, and recommendations for prevention and treatment are discussed.[ncbi.nlm.nih.gov]
  • Manifestations and Diagnosis of Venous Venous Thrombosis in Unusual Sites Victor J Marder Hylton V Joffe and Sam Schulman Prevention of Venous Thromboembolic Disease Treatment of Venous Thromboembolic Disease Overview of Arterial Thrombotic Disorders Pathophysiology[books.google.com]
  • The pathophysiology underlying warfarin-induced skin necrosis is not entirely understood.[nejm.org]
  • […] induced skin necrosis VKAs Coumarin derivatives : Bishydroxycoumarin (Dicumarol) Warfarin (Coumadin ) Analog #42 (1945) of many coumarins synthesized by Dr Link and named by him as WARFarin for the Wisconsin Alumni Research Foundation and coumARIN 6 Pathophysiology[slideplayer.com]


  • In this article the historical, clinical, and pathophysiologic features of this hypercoagulable event are reviewed, and recommendations for prevention and treatment are discussed.[ncbi.nlm.nih.gov]
  • Since treatment is generally supportive, prompt and prudent evaluation of suspicious skin lesions is necessary to prevent the serious sequelae associated with WISN.[ncbi.nlm.nih.gov]
  • There is a lack of guidelines regarding the selection of patients who need intravenous heparin, duration of intravenous heparin, and future use of warfarin in prevention and treatment of warfarin-induced skin necrosis.[ncbi.nlm.nih.gov]
  • Warfarin-induced skin necrosis is a rare but serious complication that can be prevented by routine screening for protein C, protein S or antithrombin deficiencies or for the presence of antiphospholipid antibodies before beginning warfarin therapy.[ncbi.nlm.nih.gov]
  • […] of Venous Thromboembolic Disease Treatment of Venous Thromboembolic Disease Overview of Arterial Thrombotic Disorders Pathophysiology of Atherothrombosis Prevention of Thromboembolic Stroke in Patients with Acute Thrombolytic Therapy Unusual Sites of[books.google.com]



  1. A Murad A, Daly T, Mulligan N, Lenane P. Extensive warfarin-induced skin necrosis successfully treated with negative pressure wound therapy. BMJ Case Rep. 2014;2014:bcr2013203510.
  2. Fawaz B, Candelario NM, Rochet N, Tran C, Brau C. Warfarin-induced skin necrosis following heparin-induced thrombocytopenia. Proc (Bayl Univ Med Cent). 2016;29(1):60-61
  3. Liaw TY, Chang CH. Skin necrosis complicated by warfarin-induced protein S deficiency. J Formos Med Assoc. 2014;113(10):758-759.
  4. Kakagia DD, Papanas N, Karadimas E, Polychronidis A. Warfarin-Induced Skin Necrosis. Ann Dermatol. 2014;26(1):96-98.
  5. Biscoe AL, Bedlow A. Warfarin-induced skin necrosis diagnosed on clinical grounds and treated with maggot debridement therapy. BMJ Case Rep. 2013;2013:bcr2012007455.
  6. Bhaijee F, Wainwright H, Meintjes G, et al. Warfarin-induced skin necrosis in HIV-1-infected patients with tuberculosis and venous thrombosis. S Afr Med J. 2010;100(6):372-377.
  7. Marčić M, Marčić L, Titlić M. Warfarin-Induced Skin Necrosis in Patients With Low Protein C Levels. Acta Med Iran. 2016;54(8):551-554.

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Last updated: 2019-07-11 20:13