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 Case Report www.jpgmonline.com -induced of the breast: Case report

Khalid K

Department of General ABSTRACT Surgery, Al-Iman General Warfarin-induced necrosis of the breast is an unusual complication of warfarin therapy. Since its first description Hospital, Riyadh, Kingdom of Saudi in 1943, up to 36 cases have been reported in the English literature. Close association between inherited or Arabia. functional deficiency of and S and warfarin therapy is frequently reported. A characteristic patient is an obese middle-aged female receiving treatment. The rapidly evolving painful lesion appears Correspondence: suddenly, usually within 3 to 6 days after initiation of warfarin therapy. Prevention may be achieved by identifying Kamran Khalid, the high-risk patients–female gender, middle age, obesity, and avoiding large loading doses of warfarin. Early E-mail: recognition and treatment are necessary to avoid significant long-term morbidity. Established necrosis [email protected] necessitates debridement and sometimes mastectomy. A case of warfarin-induced necrosis of the left breast mimicking inflammatory cancer is reported. Current recommendations for the prevention and treatment of Received : 03-06-04 this uncommon condition are reviewed. Review completed : 03-07-04 Accepted : 04-07-04 PubMed ID : 15623967 J Postgrad Med 2004;50:268-9 KEY WORDS: warfarin, necrosis, breast

ecrosis of the occurs in 0.01-0.1% of patients on both breasts acquired 2 years earlier (local tradition). The left N treated with warfarin or its congeners. The reported breast demonstrated a warm, moderately tender mass occupying the age range for occurrence is 16 to 93 years with female pre- subareolar region and the entire outer half with a peau d’orange ap- dominance. Usually, the sites with thick subcutaneous fat are pearance. The mass was fixed to the nipple and skin but not to the underlying fascia. Axillary lymph nodes were not palpable. Examina- affected. Breasts, buttocks, thighs, arms, hands, digits, legs, tion of the chest was suggestive of left basal consolidation. No other feet, face, nose, abdomen, back and penis are the various re- similar skin lesions were identified. Her haemoglobin was 7.8 gm%; 1,2 ported sites. Multiple lesions have been reported in 35% cases WBC count 9800/mm3; platelets 340,000/mm3 and INR was 2.8. Ul- and 20% of the lesions are symmetrical.3 The breast remains trasound of the left breast demonstrated a complex mass of mixed the most common site in females followed by the buttocks echogenecity with no evidence of collection and a high likelihood of and thighs.4-6 Since its first description by Flood and colleagues, malignancy. Breast biopsy was planned, treatment with broad-spec- up to 36 cases of warfarin-induced necrosis of the breast trum was started and the physician’s advice was obtained. (WINB) have been reported in 24 papers in the English litera- Not convinced with pulmonary embolism, the physician suggested that we continue treatment for pneumonia, discontinue warfarin, ture.4-7 To the best of the author’s knowledge this is the first and administer and (FFP). Neither report of WINB from the Kingdom of Saudi Arabia. Knowl- nor warfarin was reinstituted. Estimations of antithrombin edge of this uncommon clinical entity allows the clinician to III, protein S, Factor V Leiden and lupus anticoagulant were not avail- make an early diagnosis. Recognition and adequate treatment able. The serum values for clotting factors II, VII, X (112%, 98% and are essential to prevent significant morbidity or mortality. 126% activity of the laboratory control, respectively – ACS, Inc. USA) and protein C (83, normal 60-140) obtained 2 days after discontinu- Case History ation of warfarin and before initiation of Vitamin K and FFP were normal. On next day of admission, irregular grayish blue areas of the A 38-year-old obese Saudi female presented to the Al-Iman General skin, ecchymosis, and haemorrhagic bullae were noted overlying the Hospital, Riyadh, Saudi Arabia, with 3 days’ history of a progressively previously noticed mass. An urgent surgical debridement revealed increasing painful lump in the left breast. Since the past 2 weeks, she extensive necrosis of the skin and breast substance. Tissues were ob- was under treatment in a local hospital for left-sided lobar pneumo- tained for cultures and histology. The remaining breast was completely nia where a subsequent V/Q scan had suggested a low probability of necrotic on the following day. Second debridement resulted in total pulmonary embolism. She was heparinized employing continuous mastectomy. The cultures were negative for bacterial growth. The unfractionated heparin infusion. Three days after commencement histology was haemorrhagic necrosis of the breast skin and fat, mi- of heparin, warfarin (10 mg bolus for 2 days followed by 5 mg daily) crovascular , fibrin deposition and little inflammation. The was started and heparin was discontinued. On the fifth day after com- features were consistent with WINB. After the second debridement, mencing warfarin, the patient developed a tender mass in the left the patient demonstrated rapid clinical improvement. She was re- breast and was referred with a probable diagnosis of inflammatory ferred to a plastic surgeon and underwent split thickness skin graft- carcinoma. At presentation she was pale, tachypnoeic, tachycardic ing of the mastectomy wound. At six months follow-up, the patient and febrile (38o C). Examination revealed symmetrical cautery scars is doing well, with healed grafted area.

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268 CMYK Khalid: Warfarin-induced breast necrosis 

Discussion els.1,9 With successful treatment, the lesions follow a course of fibrosis, scarring and spontaneous healing.9 Dose-adjusted sub- Necrosis of the breast is a rare complication of warfarin therapy. cutaneous heparin therapy is recommended in those patients Typically, the condition is reported in middle-aged obese requiring long-term anticoagulation.1,9 With extreme caution, women receiving warfarin treatment for pulmonary embolism, successful recommencement of warfarin therapy has been re- deep venous thrombosis, myocardial infarction, or valvular ported.9 Allowed to run its natural course, the condition is as- heart surgery.4-10 One or both breasts are involved in 15% of the sociated with significant morbidity and deaths have been re- females.1,5 In 90% cases, the painful necrotizing lesions appear ported in severe cases.1,3,6,9,10 Characteristically, warfarin-in- within 3 to 6 days of initiation of warfarin therapy.5,9 The ini- duced breast necrosis does not respond to vitamin K therapy tial manifestation is a well localized indurated erythematous and vigorous surgical debridement is usually needed in 50% area of skin which may develop a peau d’orange appearance.1,5 cases.1,6,9 Mastectomy, unilateral or bilateral, may eventually The lesion rapidly evolves into grayish black ecchymoses. become necessary.6,9 Final closure is usually accomplished by Haemorrhagic infarcts usually follow and progress to dry gan- secondary healing, split-thickness or flap cover- grene. Early histology shows cutaneous infarcts, haemorrhages age.6,10 and breakdown of precapillary arterioles, fibrin deposits in the postcapillary venules and small veins, a distinct lack of arteri- This report describes a typical case of warfarin-induced breast olar thrombosis and no evidence of vascular or perivascular necrosis in a middle-aged obese female observed within one inflammation. Thrombosis of larger vessels in the subcutane- week of initiation of high-dose warfarin therapy. The level of ous fat results in deep necrotic sloughs and eschar forma- protein C was normal in this case and the disease was resistant tion.1,5,9,10 Once gross tissue necrosis or secondary infection to treatment with vitamin K. The traditional cosmetic cautery ensue, the biopsy becomes non-specific and non-diagnostic.9 over the breasts might have contributed as a local predispos- Less severe cases may closely mimic inflammatory carcinoma ing factor. and an early biopsy helps in excluding the diagnosis.1,6,10 The exact aetiopathogenesis of this condition and the reason for References its predilection for adipose tissue remain obscure but may be 6,9,10 multifactorial. Local factors, like variation in local tempera- 1. DeFranzo AJ, Marasco P, Argenta LC. Warfarin-induced Necrosis of the Skin. Ann Plast Surg 1995;34:203-8. ture, trauma and inadequate local perfusion, have been sug- 2. Roche-Nagle G, Robb W, Ireland A, Bouchier-Hayes D. Extensive skin necrosis as- gested.1,9,10 Previous exposure to warfarin does not predispose sociated with warfarin sodium therapy. Eur J Vasc Endovasc Surg 2003;25:481-2. 3. Warkentin TE, Whitlock RP, Teoh KH. Warfarin-associated multiple digital necrosis to the development of necrosis and recurrent lesions have been complicating heparin-induced thrombocytopenia and Raynaud’s phenomenon af- reported even in the absence of further anticoagulation ter aortic valve replacement for adenocarcinoma-associated thrombotic endocar- ditis. Am J Hematol 2004;75:56-62. 1,9 therapy. An inherited or functional deficiency of proteins C 4. Flood EP, Redish MH, Bociek SJ, Shapiro S. Thrombophlebitis migrans dissemi- 5,8-10 nate: Report of a case in which gangrene of the breast occurred. New York State and S has been reported by various authors. However, war- Jr Med 1943;43:1121-4. farin-necrosis has been reported in patients with normal levels 5. Lopez Valle CA, Hebert G. Warfarin-induced complete bilateral breast necrosis. Br 1 J Plast Surg 1992;45:606-9. of protein C and S. The necrosis may be prevented by identi- 6. Harveil JD, Furman RL. Recurrent coumadin-induced soft tissue necrosis resulting fying high-risk patients and avoiding large loading doses of in mastectomy. Mil Med 1993;158:283-4. 1 7. Isenberg JS, Tu Q, Rainey W. Mammary gangrene associated with warfarin inges- warfarin. The initial treatment remains supportive and con- tion. Ann Plast Surg 1996;37:553-5. servative. Although, discontinuation of warfarin has not been 8. Parsi K, Younger I, Gallo J. Warfarin-induced skin necrosis associated with acquired . Australas J Dermatol 2003;44:57-61. shown to alter the outcome it is generally recommended. 9. Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg 2000;87:266-72. Heparin should be started in high doses and vitamin K and 10. Ad-El DD, Meirovitz A, Weinberg A, Kogan L, Arieli D, Neuman A, et al. Warfarin FFP should be administered to restore protein C and S lev- skin necrosis: Local and systemic factors. Br J Plast Surg 2000;53:624-6.

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