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Warfarin-induced breast necrosis.
(Portuguese PDF version)

Marcio Miyamotto¹, Ricardo César Rocha Moreira², Jeferson Freitas Toregeani³, Fabiano Luiz Erzinger³, Heitor Lagos⁴

1. Vascular and endovascular surgeon, Serviço de Cirurgia Vascular Prof. Dr. Elias Abrão, Curitiba, PR, Brazil.
2. MSc and PhD in Clinical Surgery, Universidade Federal do Paraná, Brazil. Chief of Serviço de Cirurgia Vascular Prof. Dr. Elias Abrão, Curitiba, PR, Brazil.
3. Resident, Serviço de Cirurgia Vascular Prof. Dr. Elias Abrão, Curitiba, PR, Brazil.
4. Clinician, Hospital Nossa Senhora das Graças, Curitiba, PR, Brazil.

Correspondence:
Marcio Miyamotto
Rua Padre Anchieta, 1995/2004
CEP 80730-000 - Curitiba, PR
Brazil
Phone: +55 41 339.2312/244.8787
E-mail: miyamotto@brturbo.com

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ABSTRACT

Warfarin-induced skin and subcutaneous fat necrosis is a rare complication of anticoagulant therapy. The authors report the case of a 40-year-old obese female with protein S deficiency, who developed bilateral breast necrosis using warfarin for deep venous thrombosis and pulmonary embolism therapy.

Key-words: warfarin, necrosis, venous thrombosis.
Palavras-chave: warfarina, necrose, trombose venosa.

J Vasc Br 2004;3(1):52-4

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Oral anticoagulants were introduced into clinical practice during the 1940's¹ and, since then, have been widely used in cardiovascular disorders. According to Chan et al., it was Verhagen who established the relation between skin necrosis and the use of warfarin, in 1954.² Approximately 300 cases have been reported worldwide since then. Skin and subcutaneous fat necrosis has a prevalence of 0.01% to 0.1%, especially during the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE).^2,3 The authors report the case of bilateral breast necrosis induced by oral anticoagulant during the treatment of DVT.

CASE REPORT

Female, 40-year-old, obese, sedentary, smoking patient, with arterial hypertension under control. She was admitted with bilateral deep venous thrombosis in lower limbs, which was confirmed by Doppler ultrasound. Initially, the patient was treated with continuous IV intravenous infusion of unfractionated heparin (25,000 U/day) by infusion pump. The dose was increased on the second day (35,000 U/day) according to the activated partial thromboplastin time (aPTT). Satisfactory levels of aPTT were not achieved, despite the increasing doses of heparin. Thus, low-molecular weight heparin (LMWH) therapy was started (1mg/kg every 12 hours), and the possibility of thrombophilia was investigated. On the 4th day of anticoagulant therapy with LMWH, sodium warfarin was introduced at 10 mg/day, which was then increased to 12.5 mg/day in order to keep the international normalized ratio (INR) between 2 and 3. Then, protein S deficiency was confirmed, with 24% of activity.

On the 12th day of treatment with warfarin, the patient presented pain, hyperemia and extensive bilateral ecchymosis in her breasts (with approximately 7 cm of diameter). The use of warfarin was interrupted (INR 3), fresh frozen plasma and vitamin K were introduced, and the use of LMWH was resumed. After 72 hours, the areas of ecchymoses increased. Nine days after that, bilateral breast necrosis was evident (Figure 1). The patient underwent several surgical debridements (Figure 2) and was discharged on the 28th day with a plane for placement of breast prostheses.

Figure 1 - Bilateral breast necrosis.

Figure 2 - Post-debridement.

DISCUSSION

Warfarin-induced skin necrosis was first observed by Food et al. in 1943. However, in that occasion, it was misdiagnosed as superficial thrombophlebitis migrans. It was only in the end of the 1950's that the association between skin necrosis and the use of oral anticoagulants was established.^1,4

The prevalence of warfarin-induced skin necrosis in higher among obese females, with protein C deficiency (50%).³ Protein S deficiency, antithrombin III deficiency, factor V Leiden and antiphospholipid antibody are also related to this syndrome.^4,5 Although oral anticoagulants are prescribed for many situations, necrosis occur more frequently in patients treated for DVT and PE, with daily doses of warfarin greater than 10 mg.²

The most frequent affected sites are those with abundant subcutaneous fat, such as breasts, buttocks and thighs. The trunk, face and extremities can also be affected. Penis involvement is extremely rare.^2,3,6-9 The disease typically begins with a local sudden pain, edema and erythema sharply demarcating the affected area. Within 24 to 48 hours, the scenario evolves into petechiae, hemorrhagic lesions, bullae formations, characterizing that the lesion is irreversible.² Necrosis generally appears between days 3 and 6 after the initiation of warfarin therapy.⁵

The mechanism of warfarin-induced skin necrosis is still unknown. Proteins C and S have been implicated in such disease, once coumarin derivatives inhibit the synthesis of such proteins in the liver, rapidly reducing their levels.^2,4,5

Histologically, the lesions do not affect arteries. The most frequent sites involved are postcapillary vessels, venules and eventually veins in subcutaneous fat. Such lesions are hemorrhagic infarctions of the microcirculation of the skin and subcutaneous fat. Nalbadian et al. reported rupture of capillaries, causing petechiae and ecchymoses and vein and venule thrombosis due to local stasis.^2,3,5,6,10

Treatment in the initial stage can prevent the progress of the disease. Interruption of oral anticoagulant and infusion of fresh frozen plasma and vitamin K are recommended. This stimulate proteins C and S synthesis by the liver, so that their levels increase.^2,3 In case of protein C deficiency, replacement should be made with monoclonal antibody, if available. Once the necrosis appears, not much can be done. Despite adequate treatment, more than 50% of patients will need surgical debridement or even amputation and mutilation.^2,5,8,9

Skin necrosis caused by oral anticoagulants is a rare but catastrophic condition. The best approach to such cases is precocious diagnosis. The staff should be aware of every sign or risk factor which might be associated with such syndrome. Although it is generally not a lethal complication, most patients end up having stigmas throughout the rest of their lives.

REFERENCES

1. Food EP, Redish MH, Bociek SJ, Shapiro S. Thrombophlebitis migrans disseminate: report of a case in which gangrene of the breast occurred. Observations on the therapeutic use of dicumarol (3,3 methylenebis(4-hidroxicoumarin)). N Y State J Med 1943;43:1121-4.

2. Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg 2000;87:266-72.

3. Jillella AP, Lutcher CL. Reinstituing warfarin in patients who develop warfarin skin necrosis. Am J Hematology 1996;52:117-9.

4. Ad-El DD, Meirovitz A, Weinberg A, et al. Warfarin skin necrosis: local and systemic factors. Br J Plast Surg 2000;53:624-6.

5. Essex DW, Wynn SS, Jin DK. Late-onset warfarin skin necrosis: case report and review of the literature. Am J Hematology 1998;57:233-7.

6. Freeman BD, Schmieg RE, McGrath S, Buchman TG, Zehnbauer BA. Factor V Leiden mutation in a patient with warfarin-associated skin necrosis. Surgery 2000;127(5):595-6.

7. Haimovici H, Bergan JJ. Coumadin-induced skin necrosis versus venous gangrene of the extremities. J Vasc Surg 1987;5:655-6.

8. De Franzo AJ, Marasco P, Argenta LC. Warfarin-induced necrosis of the skin. Ann Plast Surgery 1995;34:203-8.

9. Sternberg ML, Pettyjohn FS. Warfarin sodium-induced skin necrosis. Ann Emerg Med 1995;26:94-7.

10. Nalbadian RM, Mader IJ, Barret JL, Pearce JF, Rupp EC. Petechiae, ecchymoses, and necrosis of skin induced by coumarin congeners. Rare, occasionally lethal complication of anticoagulant therapy. JAMA 1965;192:107-12.