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Warfarin skin necrosis: local and systemic factors
624 2. Wijnmaalen A, Van Ooijen B, Van Geel BN, Henzen-Logmans SC, Treurniet-Donker AD. Angiosarcoma of the breast following lumpectomy, axillary lymph node dissection, and radiotherapy for primary breast cancer: three case reports and a review of the literature. Int J Radiat Oncol Biol Phys 1993; 26: 135-9. 3. Hunter TB, Martin PC, Dietzen CD, Tyler LT. Angiosarcoma of the breast: two case reports and a review of the literature. Cancer 1985; 56: 2099-106. 4. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema: a report of six cases in elephantiasis chirurgica. Cancer 1948; 1: 64-81. 5. Kuten A, Sapir D, Cohen Y, Haim N, Borovik R, Robinson E. Postirradiation soft tissue sarcoma occurring in breast cancer patients: report of seven cases and results of combination chemotherapy. J Surg Oncol 1985; 28: 168-71. 6. Givens SS, Ellerbroek NA, Butler JJ, Libshitz HI, Hortobagyi GN, McNeese MD. Angiosarcoma arising in an irradiated breast: a case report and review of the literature. Cancer 1989; 64: 2214-16.
British Journal of Plastic Surgery 7. Turner WH, Greenall MJ. Sarcoma induced by radiotherapy after breast conservation surgery. Br J Surg 1991; 78: 1317-18.
The Authors R. James I. Colville MSc, FRCS, Specialist Registrar in Plastic Surgery Alex Ramsden FRCS, SHO in Plastic Surgery Archie Malcolm MB, ChB, FRCPath, Professor of Pathology Nell R. McLean MD, FRCS, Consultant Head and Neck/Plastic and Reconstructive Surgeon Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LE, UK. Correspondence to James Colville. Paper received 4 January 2000. Accepted 5 June 2000, after revision.
British Journal of Plastic Surgery (2000), 53
9 2000 The BritishAssociationof Plastic Surgeons doi:10.t054/bjps.2000.3402
Warfarin skin necrosis: local and systemic factors D. D. Ad-E1, A. Meirovitz*, A. Weinberg, L. Kogan, D. Arieli, A. Neuman and D. Linton*
Department of Plastic and Reconstructive Surgery; and *Medical Intensive Care Unit, Hadassah University Hospital, Jerusalem, Israel SUMMARY. Warfarin induced skin necrosis occurs in 0.01-0.1% of warfarin treated patients. The usual presentation is that of painful lesions developing in obese women after the initiation of warfarin treatment. The lesions usually evolve into full thickness skin necrosis within a few days. Although the exact mechanism is not totally clear, low levels of Protein C or S, either functional or inherited, are associated with many of the cases. We report the case of a 17-year-old patient treated with warfarin because of iliofemoral deep vein thrombosis post abortion. The patient developed several huge haemorrhagic blisters on the affected leg. The condition rapidly developed into full thickness skin and fat necrosis. The necrotic lesions were excised and eventually covered with skin graft. The combination of the patient tendency towards hyper-coagulation and the local factors is discussed. 9 2000 The British Association of Plastic Surgeons
Keywords: skin necrosis, warfarin.
Warfarin is used extensively for the treatment and prophylaxis of thromboembolism. The first reports of a possible connection between the drug and skin damage were by Flood et al I who described a migratory thrombophlebitis in 1943 and Verhagen 2 who was the first to describe skin necrosis in 1954. To date, more than 200 cases have been described in the literature. The phenomenon occurs in 0.01-0.1% of patients receiving warfarin therapy. 3 The common clinical course is characterised by a rapidly developing skin lesion, 3-10 days after the initiation of warfarin therapy. The lesions first appear as localised areas of erythema with a 'peau d'orange' appearance. Petechiae, ecchymoses and haemorrhagic bullae soon develop. The affected skin undergoes haemorrhagic infarction and a dark eschar develops over the necrotic area. 3'4 The necrotic lesions progress to full thickness skin loss with variable necrosis of the subcutaneous layers. The affected areas are usually the buttocks, thighs and breasts ~ where heavy subcutaneous fat layers exist. The local factors suggested to contribute to the event are variation in local temperature, trauma and local perfusion. 5-7 There are no reports of other local factors
affecting or contributing to the phenomenon. Multiple lesions are found in 35% of patients) The reported female to male ratio is 9:1 and the most commonly seen patient is an obese woman treated by warfarin for deep vein thrombosis (DVT) or myocardial ischaemia. 3 The typical histological picture includes haemorrhage and damage to the precapillary arterioles, thrombosis of dermal and subcutaneous vessels, dilatation of small venules and widespread oedema. 8 An infiltrate of fibroblasts, neutrophils and lymphocytes may be found. In more advanced stages, coagulative necrosis and thrombosed veins are also seen. The pathogenesis of the phenomenon is not totally clear. Frequent association functional or inherited low levels of Protein C or S with the initiation of the warfarin treatment is thought to contribute to the relative hyper-coagulability state that affects the small vessels in the skin. s Treatment3,4,8 is based on discontinuation of the warfarin and a change to heparin. Local wound care, debridement of necrotic tissues and skin grafting are the local therapeutic measures. It has been observed that even with early diagnosis, full thickness skin necrosis is not always preventable. 9-tl
Warfarin skin necrosis
625
Figure 1--The patient upon admission. Case report A 17-year-old female patient was transferred to our hospital with markedly oedematous legs and several huge haemorrhagic blisters on her legs (Fig. 1). The patient had a missed abortion three weeks earlier and underwent termination of pregnancy in another hospital. A few days after the procedure the patient developed left iliofemoral vein thrombosis proven by Doppler ultrasound and was started on heparin therapy. The heparin was then stopped and the patient was started on warfarin (probably without parallel administration of both). Three days after initiation of the warfarin therapy, progressive swelling of her left leg accompanied by subcutaneous haemorrhages developed. The patient was then transferred to our hospital. Her family history revealed that her grandmother and mother suffered recurrent DVT. On physical examination her left leg was markedly oedematous with a 15cm difference in the diameter (20cm above the knee) between the two legs. Several huge blisters appeared on the leg (Fig. 1). Haematological investigation showed Hgb 9.1gr/dl, WBC 29700 (74% neutrophils), Plt 280000, PT 27%, PTT 57 s, INR 4.06, Fib 330mg% (n = 150-400mg%), FDP 120mcg/ml (n < 10 mcg/ml). CT-angiography showed blood clots in the left external iliac vein, left common femoral vein and left greater saphenous vein. Duplex confirmed DVT of the left common femoral vein with good arterial flow. Blood and urinary cultures were negative. In the coagulation work up the patient was found to be heterozygous for Activated Protein C (APC) resistance. The patient was admitted to ICU and received fresh frozen plasma and full dose heparin therapy to correct her clotting abnormalities. She was started empirically on IV Augmentin. Three days after admission the patient was taken to theatre where full thickness skin necrosis was found underneath the blisters, which were treated by intensive local wound care. The patient underwent further debridement and eventual coverage of the left thigh and ankle defects by split thickness skin grafts. The patient was discharged from the hospital 5 weeks after admission in a good condition, on Enoxaparin treatment and with healing wounds (Fig. 2).
Discussion In any case of skin necrosis coincident with a thrombotic event and warfarin therapy, making the correct diagnosis is crucial. Microembolisation, necrotising fasciitis and purpura fulminans can all appear in similar settings especially in very sick patients, lz'13 Purpura fulminans occurs mainly in the paediatric population as a result of a severe meningococcal infection. The natural progression and the
Figure 2--The patient 2 weeks after discharge. appearance of necrotising fasciitis is different from warfarin necrosis with mild colour changes in the skin but swelling and purulence in the subcutis. Microembolisation occurs in patients with septicaemia and usually appears in the toes and fingers. The treatment o f microembolisation and purpura fulminans is based on dealing with the cause while the treatment of necrotising fasciitis is immediate surgical debridement and drainage. Warfarin necrosis in the breast skin and fat can mimic inflammatory carcinoma, 5 but the rapid progression of the skin lesions is different. Warfarin causes vitamin K deficiency by preventing the reduction of vitamin K epioxides in the liver. It slows thrombin formation and clot formation by impairing the biologic activity of prothrombin complex and is mainly used to prevent recurrent thromboembolic event (Fig. 3). 14 Protein C, a vitamin K dependent protein, and its activated forms are essential in the process of thrombo and fibrinolysis (Fig. 3); its deficiency can lead to hyper-coagulable state (Fig. 3) and was described in connection with warfarin induced skin necrosis. 15 Activated protein C (APC, Protein Ca) is a potent anticoagulant that inactivates factors V and VIII. APC resistance is caused by a mutation in factor V (Leiding factor), which makes it resistant to inactivation by APC. APC resistance was found to occur with high frequency among patients with thromboembolic phenomena. 15 The combination of initiation of warfarin therapy, which causes reduction in the levels of Protein C and S, the non-parallel heparin therapy, the genetic predisposition and the tissue necrosis are highly suggestive of warfarin necrosis. The role of local factors affecting the skin necrosis after warfarin therapy was never fully investigated. The microcirculation of fat was investigated but never implicated to fat ischaemia and necrosis. ~6 The assumption that heavy fat layers contribute to the skin damage is logical since the
626
British Journal of Plastic Surgery
Activators Y
Inhibitors
..... Vascular Endothelium,i
Vessel injury':- ..........v.WF..~ 14" . . . . . . . . . ,'pGiz. . . . . . | Heparin . . . . : Thrombomodulin- ~'-," Platelet Adhesion ',
',
Contact Activation Tissue Factor ......... ~ ":
['~ . . . . . . . . .
. / ']-~-,,,"-, . . . . . .
, ,
i CT-inhibitor ," Protein C - , I - "
i
,"
Factor V ..................~0--:::22~.~. . . . . . . , Antithrombin II1~"" ,' Thrombin .-" ADP ............... ~-,i ..... Collagen ......"-"1~Platelet Aggregation.,1 . . . . . . +
Fibrin Formation Factor Xllla ....................... D"I"I"-Activator" .Tjs.su_ _e... Plasminogen
Recanalisation Healing Figure 3--Thrombo and fibrinolysis. fat v a s c u l a r i t y is d i m i n i s h e d . T h i s c o n n e c t i o n b e t w e e n D V T a n d skin n e c r o s i s is w e l l d e s c r i b e d 17 a n d c a n b e e x p l a i n e d b y b l o o d stasis, tissue o e d e m a a n d e l e v a t e d e x t r a c e l l u l a r pressure. T h i s c a n c a u s e relative d i m i n u t i o n in the capillary b l o o d flow, e p i d e r m o l y s i s a n d full thickness tissue loss. T h e fact t h a t m o s t o f the d a m a g e w a s a r o u n d the left leg, w h o s e d e e p v e n o u s s y s t e m was b l o c k e d , c a n also b e e x p l a i n e d b y the local h y p e r - c o a g u lation a n d o e d e m a that c o n t r i b u t e d to tissue i s c h a e m i a a n d to the u n u s u a l features p r e s e n t e d in this case.
5. Lopez Valle CA, Hebert G. Warfarin-induced complete bilateral breast necrosis. Br J Plast Surg 1992; 45: 606-9. 6. Broekmans AW, Bertina RM, Loeliger EA, Hofmann V, Klingmann HG. Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 1983; 49: 251. 7. Comp PC, Elrod JP, Karzenski S. Warfarin-induced skin necrosis. Semin Thromb Hemost 1990; 16: 293-8. 8. Rose VL, Kwaan HC, Williamson K, Hoppensteadt D, Walenga J, Fareed J. Protein C antigen deficiency and warfarin necrosis. Am J Clin Pathol 1986; 86: 653-5. 9. Hmnphries JE, Gardner JH, Connelly JE. Warfarin skin necrosis: recurrence in the absence of anticoagulant therapy. Am J Hematol 1991; 37: 197-200. 10. Wynn SS, Jin DK, Essex DW. Warfarin-induced skin necrosis occurring four days after discontinuation of warfarin. Haemostasis 1997; 27: 246-50. 11. Cole MS, Minifee PK, Wolma FJ. Coumarin necrosis - a review of the literature. Surgery 1988; 103: 271-7. 12. Cram DL, Soley RL. Purpura fulminans. Br J Dermatol 1968; 80: 323-7. 13. Gozal D, Ziser A, Shupak A, Ariel A, Melamed Y. Necrotizing fasciitis. Arch Surg 1986; 121: 233-5. 14. Vitamin K antagonist. In: Katzung BG, ed. Drug Therapy, 2nd Ed. Appelton & Lange (international), 1991: 96--100. 15. Protein C deficiency: inherited resistance to the anticoagulant activity of activated Protein C. In: Hoffman RH, Benz EJ Jr., Shatill SJ, Furie B, Cohen HJ, Silverstein LE. Hematology, Basic Principles and Practice, 2nd Ed. New York: Churchill Livingstone, 1995: 1785-9. 16. Crandall DL, Hausman GJ, Kral JG. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 1997; 4:211-32. 17. Brennan M, Morgan I-IJ, George A. Deep venous thrombosis with localized skin necrosis. J Tenn Med Assoc 1986; 79: 210.
The Authors D. D. Ad-EI MD A. Weinberg L. Kogan D. Arieli A. Neuman
References
Department of Plastic and Reconstructive Surgery
1. Flood EP, Redish MH, Bociek SJ, Shapiro S. Thrombophlebitis migrans disseminata: report of a case in which gangrene of a breast occurred: observations on the therapeutic use of dicumarol (3,3' methylenebis (4-hydroxycoumarin)). NY State J Med 1943; 43: 1121--4. 2. Verhagen H. Local haemorrhage and necrosis of the skin and underlying tissues, during anti-coagulant therapy with dicumarol or dicumacyl. Acta Med Scand 1954; 148: 453-62. 3. DeFranzo AJ, Marasco P, Argenta LC. Warfarin-induced necrosis of the skin. Ann Plast Surg 1995; 34: 203-8. 4. Steruberg ML, Pettyjohn FS. Warfarin sodium-induced skin necrosis. Ann Emerg Med 1995; 26: 94-7.
A. Meirovitz D. Linton Medical Inten]sive Care Unit Hadassah University Hospital, Ein Kerem, PO Box 12000, Jerusalem 91120, Israel. Correspondence to Dean D. Ad-E1. Paper received 1 October 1999. Accepted 5 June 2000, after revision.
British Journal of Plastic Surgery 7. Turner WH, Greenall MJ. Sarcoma induced by radiotherapy after breast conservation surgery. Br J Surg 1991; 78: 1317-18.
The Authors R. James I. Colville MSc, FRCS, Specialist Registrar in Plastic Surgery Alex Ramsden FRCS, SHO in Plastic Surgery Archie Malcolm MB, ChB, FRCPath, Professor of Pathology Nell R. McLean MD, FRCS, Consultant Head and Neck/Plastic and Reconstructive Surgeon Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LE, UK. Correspondence to James Colville. Paper received 4 January 2000. Accepted 5 June 2000, after revision.
British Journal of Plastic Surgery (2000), 53
9 2000 The BritishAssociationof Plastic Surgeons doi:10.t054/bjps.2000.3402
Warfarin skin necrosis: local and systemic factors D. D. Ad-E1, A. Meirovitz*, A. Weinberg, L. Kogan, D. Arieli, A. Neuman and D. Linton*
Department of Plastic and Reconstructive Surgery; and *Medical Intensive Care Unit, Hadassah University Hospital, Jerusalem, Israel SUMMARY. Warfarin induced skin necrosis occurs in 0.01-0.1% of warfarin treated patients. The usual presentation is that of painful lesions developing in obese women after the initiation of warfarin treatment. The lesions usually evolve into full thickness skin necrosis within a few days. Although the exact mechanism is not totally clear, low levels of Protein C or S, either functional or inherited, are associated with many of the cases. We report the case of a 17-year-old patient treated with warfarin because of iliofemoral deep vein thrombosis post abortion. The patient developed several huge haemorrhagic blisters on the affected leg. The condition rapidly developed into full thickness skin and fat necrosis. The necrotic lesions were excised and eventually covered with skin graft. The combination of the patient tendency towards hyper-coagulation and the local factors is discussed. 9 2000 The British Association of Plastic Surgeons
Keywords: skin necrosis, warfarin.
Warfarin is used extensively for the treatment and prophylaxis of thromboembolism. The first reports of a possible connection between the drug and skin damage were by Flood et al I who described a migratory thrombophlebitis in 1943 and Verhagen 2 who was the first to describe skin necrosis in 1954. To date, more than 200 cases have been described in the literature. The phenomenon occurs in 0.01-0.1% of patients receiving warfarin therapy. 3 The common clinical course is characterised by a rapidly developing skin lesion, 3-10 days after the initiation of warfarin therapy. The lesions first appear as localised areas of erythema with a 'peau d'orange' appearance. Petechiae, ecchymoses and haemorrhagic bullae soon develop. The affected skin undergoes haemorrhagic infarction and a dark eschar develops over the necrotic area. 3'4 The necrotic lesions progress to full thickness skin loss with variable necrosis of the subcutaneous layers. The affected areas are usually the buttocks, thighs and breasts ~ where heavy subcutaneous fat layers exist. The local factors suggested to contribute to the event are variation in local temperature, trauma and local perfusion. 5-7 There are no reports of other local factors
affecting or contributing to the phenomenon. Multiple lesions are found in 35% of patients) The reported female to male ratio is 9:1 and the most commonly seen patient is an obese woman treated by warfarin for deep vein thrombosis (DVT) or myocardial ischaemia. 3 The typical histological picture includes haemorrhage and damage to the precapillary arterioles, thrombosis of dermal and subcutaneous vessels, dilatation of small venules and widespread oedema. 8 An infiltrate of fibroblasts, neutrophils and lymphocytes may be found. In more advanced stages, coagulative necrosis and thrombosed veins are also seen. The pathogenesis of the phenomenon is not totally clear. Frequent association functional or inherited low levels of Protein C or S with the initiation of the warfarin treatment is thought to contribute to the relative hyper-coagulability state that affects the small vessels in the skin. s Treatment3,4,8 is based on discontinuation of the warfarin and a change to heparin. Local wound care, debridement of necrotic tissues and skin grafting are the local therapeutic measures. It has been observed that even with early diagnosis, full thickness skin necrosis is not always preventable. 9-tl
Warfarin skin necrosis
625
Figure 1--The patient upon admission. Case report A 17-year-old female patient was transferred to our hospital with markedly oedematous legs and several huge haemorrhagic blisters on her legs (Fig. 1). The patient had a missed abortion three weeks earlier and underwent termination of pregnancy in another hospital. A few days after the procedure the patient developed left iliofemoral vein thrombosis proven by Doppler ultrasound and was started on heparin therapy. The heparin was then stopped and the patient was started on warfarin (probably without parallel administration of both). Three days after initiation of the warfarin therapy, progressive swelling of her left leg accompanied by subcutaneous haemorrhages developed. The patient was then transferred to our hospital. Her family history revealed that her grandmother and mother suffered recurrent DVT. On physical examination her left leg was markedly oedematous with a 15cm difference in the diameter (20cm above the knee) between the two legs. Several huge blisters appeared on the leg (Fig. 1). Haematological investigation showed Hgb 9.1gr/dl, WBC 29700 (74% neutrophils), Plt 280000, PT 27%, PTT 57 s, INR 4.06, Fib 330mg% (n = 150-400mg%), FDP 120mcg/ml (n < 10 mcg/ml). CT-angiography showed blood clots in the left external iliac vein, left common femoral vein and left greater saphenous vein. Duplex confirmed DVT of the left common femoral vein with good arterial flow. Blood and urinary cultures were negative. In the coagulation work up the patient was found to be heterozygous for Activated Protein C (APC) resistance. The patient was admitted to ICU and received fresh frozen plasma and full dose heparin therapy to correct her clotting abnormalities. She was started empirically on IV Augmentin. Three days after admission the patient was taken to theatre where full thickness skin necrosis was found underneath the blisters, which were treated by intensive local wound care. The patient underwent further debridement and eventual coverage of the left thigh and ankle defects by split thickness skin grafts. The patient was discharged from the hospital 5 weeks after admission in a good condition, on Enoxaparin treatment and with healing wounds (Fig. 2).
Discussion In any case of skin necrosis coincident with a thrombotic event and warfarin therapy, making the correct diagnosis is crucial. Microembolisation, necrotising fasciitis and purpura fulminans can all appear in similar settings especially in very sick patients, lz'13 Purpura fulminans occurs mainly in the paediatric population as a result of a severe meningococcal infection. The natural progression and the
Figure 2--The patient 2 weeks after discharge. appearance of necrotising fasciitis is different from warfarin necrosis with mild colour changes in the skin but swelling and purulence in the subcutis. Microembolisation occurs in patients with septicaemia and usually appears in the toes and fingers. The treatment o f microembolisation and purpura fulminans is based on dealing with the cause while the treatment of necrotising fasciitis is immediate surgical debridement and drainage. Warfarin necrosis in the breast skin and fat can mimic inflammatory carcinoma, 5 but the rapid progression of the skin lesions is different. Warfarin causes vitamin K deficiency by preventing the reduction of vitamin K epioxides in the liver. It slows thrombin formation and clot formation by impairing the biologic activity of prothrombin complex and is mainly used to prevent recurrent thromboembolic event (Fig. 3). 14 Protein C, a vitamin K dependent protein, and its activated forms are essential in the process of thrombo and fibrinolysis (Fig. 3); its deficiency can lead to hyper-coagulable state (Fig. 3) and was described in connection with warfarin induced skin necrosis. 15 Activated protein C (APC, Protein Ca) is a potent anticoagulant that inactivates factors V and VIII. APC resistance is caused by a mutation in factor V (Leiding factor), which makes it resistant to inactivation by APC. APC resistance was found to occur with high frequency among patients with thromboembolic phenomena. 15 The combination of initiation of warfarin therapy, which causes reduction in the levels of Protein C and S, the non-parallel heparin therapy, the genetic predisposition and the tissue necrosis are highly suggestive of warfarin necrosis. The role of local factors affecting the skin necrosis after warfarin therapy was never fully investigated. The microcirculation of fat was investigated but never implicated to fat ischaemia and necrosis. ~6 The assumption that heavy fat layers contribute to the skin damage is logical since the
626
British Journal of Plastic Surgery
Activators Y
Inhibitors
..... Vascular Endothelium,i
Vessel injury':- ..........v.WF..~ 14" . . . . . . . . . ,'pGiz. . . . . . | Heparin . . . . : Thrombomodulin- ~'-," Platelet Adhesion ',
',
Contact Activation Tissue Factor ......... ~ ":
['~ . . . . . . . . .
. / ']-~-,,,"-, . . . . . .
, ,
i CT-inhibitor ," Protein C - , I - "
i
,"
Factor V ..................~0--:::22~.~. . . . . . . , Antithrombin II1~"" ,' Thrombin .-" ADP ............... ~-,i ..... Collagen ......"-"1~Platelet Aggregation.,1 . . . . . . +
Fibrin Formation Factor Xllla ....................... D"I"I"-Activator" .Tjs.su_ _e... Plasminogen
Recanalisation Healing Figure 3--Thrombo and fibrinolysis. fat v a s c u l a r i t y is d i m i n i s h e d . T h i s c o n n e c t i o n b e t w e e n D V T a n d skin n e c r o s i s is w e l l d e s c r i b e d 17 a n d c a n b e e x p l a i n e d b y b l o o d stasis, tissue o e d e m a a n d e l e v a t e d e x t r a c e l l u l a r pressure. T h i s c a n c a u s e relative d i m i n u t i o n in the capillary b l o o d flow, e p i d e r m o l y s i s a n d full thickness tissue loss. T h e fact t h a t m o s t o f the d a m a g e w a s a r o u n d the left leg, w h o s e d e e p v e n o u s s y s t e m was b l o c k e d , c a n also b e e x p l a i n e d b y the local h y p e r - c o a g u lation a n d o e d e m a that c o n t r i b u t e d to tissue i s c h a e m i a a n d to the u n u s u a l features p r e s e n t e d in this case.
5. Lopez Valle CA, Hebert G. Warfarin-induced complete bilateral breast necrosis. Br J Plast Surg 1992; 45: 606-9. 6. Broekmans AW, Bertina RM, Loeliger EA, Hofmann V, Klingmann HG. Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 1983; 49: 251. 7. Comp PC, Elrod JP, Karzenski S. Warfarin-induced skin necrosis. Semin Thromb Hemost 1990; 16: 293-8. 8. Rose VL, Kwaan HC, Williamson K, Hoppensteadt D, Walenga J, Fareed J. Protein C antigen deficiency and warfarin necrosis. Am J Clin Pathol 1986; 86: 653-5. 9. Hmnphries JE, Gardner JH, Connelly JE. Warfarin skin necrosis: recurrence in the absence of anticoagulant therapy. Am J Hematol 1991; 37: 197-200. 10. Wynn SS, Jin DK, Essex DW. Warfarin-induced skin necrosis occurring four days after discontinuation of warfarin. Haemostasis 1997; 27: 246-50. 11. Cole MS, Minifee PK, Wolma FJ. Coumarin necrosis - a review of the literature. Surgery 1988; 103: 271-7. 12. Cram DL, Soley RL. Purpura fulminans. Br J Dermatol 1968; 80: 323-7. 13. Gozal D, Ziser A, Shupak A, Ariel A, Melamed Y. Necrotizing fasciitis. Arch Surg 1986; 121: 233-5. 14. Vitamin K antagonist. In: Katzung BG, ed. Drug Therapy, 2nd Ed. Appelton & Lange (international), 1991: 96--100. 15. Protein C deficiency: inherited resistance to the anticoagulant activity of activated Protein C. In: Hoffman RH, Benz EJ Jr., Shatill SJ, Furie B, Cohen HJ, Silverstein LE. Hematology, Basic Principles and Practice, 2nd Ed. New York: Churchill Livingstone, 1995: 1785-9. 16. Crandall DL, Hausman GJ, Kral JG. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 1997; 4:211-32. 17. Brennan M, Morgan I-IJ, George A. Deep venous thrombosis with localized skin necrosis. J Tenn Med Assoc 1986; 79: 210.
The Authors D. D. Ad-EI MD A. Weinberg L. Kogan D. Arieli A. Neuman
References
Department of Plastic and Reconstructive Surgery
1. Flood EP, Redish MH, Bociek SJ, Shapiro S. Thrombophlebitis migrans disseminata: report of a case in which gangrene of a breast occurred: observations on the therapeutic use of dicumarol (3,3' methylenebis (4-hydroxycoumarin)). NY State J Med 1943; 43: 1121--4. 2. Verhagen H. Local haemorrhage and necrosis of the skin and underlying tissues, during anti-coagulant therapy with dicumarol or dicumacyl. Acta Med Scand 1954; 148: 453-62. 3. DeFranzo AJ, Marasco P, Argenta LC. Warfarin-induced necrosis of the skin. Ann Plast Surg 1995; 34: 203-8. 4. Steruberg ML, Pettyjohn FS. Warfarin sodium-induced skin necrosis. Ann Emerg Med 1995; 26: 94-7.
A. Meirovitz D. Linton Medical Inten]sive Care Unit Hadassah University Hospital, Ein Kerem, PO Box 12000, Jerusalem 91120, Israel. Correspondence to Dean D. Ad-E1. Paper received 1 October 1999. Accepted 5 June 2000, after revision.