SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 16, NO. 4, 1990
Warfarin-Induced Skin Necrosis
Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This review will discuss the clinical presentation, natural history, incidence, and possible etiologies of this condition as well as the limited therapeutic options available to the clinician. The term "warfarin-induced skin necrosis" will be used throughout this review although similar necrotic skin lesions have been observed following a variety of other oral anticoagulant compounds. Although the term "coumarin-induced skin necrosis" is found in the medical literature, it is probably less suitable. Coumarin is the parent compound from which many oral anticoagulants, including warfarin, are derived. However, coumarin itself has no anticoagulant activity and is not used clinically for that purpose.1'2
CLINICAL PRESENTATION Warfarin-induced skin necrosis presents as a discolored area of skin that often progresses to frank necrosis of the skin and the underlying fatty tissue. The clinical presentation of warfarin-induced skin necrosis has been described in over 300 articles and case reports over the last 35 years3-5 and has been the subject of several comprehensive reviews. 6-10 Warfarin-induced skin necrosis may initially present as a painful area of skin on the third to sixth day following the initiation of oral anticoagulation. The skin has been described as "erythematous," "flushed," or "darkened," and the patient may complain of a sensation of pressure in the affected area.
Petechial hemorrhages may next appear in the skin with sharp demarcation of the borders. Hemorrhagic bullae may be present at this stage. The affected skin then becomes necrotic and blackened and eschar appears. The necrotic skin may separate from the underlying tissues. The resulting wound is frequently repaired surgically or may be allowed to heal spontaneously. The diagnosis of warfarin-induced skin necrosis is complicated by the frequent occurrence of subcutaneous hemorrhage in patients on oral anticoagulants. Hemorrhagic complications are not particularly common early in the course of oral anticoagulation and do not result in necrosis of the skin or underlying tissue. Warfarin-induced skin necrosis occurs more frequently in females (over 75% of cases). The breasts appear to be most frequently affected,11 followed by the thighs,12 buttocks, and occasionally the legs.13 The distribution in men is similar with sparing of the breasts; necrosis of the penis has been reported. 3,14-19 No convincing arguments have been advanced to explain the apparent predilection for areas, such as the breasts, with underlying fatty tissue. The majority of lesions occur between the third and sixth day of oral anticoagulant therapy. In one patient, skin necrosis occurred 3 years after the initiation of an oral anticoagulant20 and in another case after 17 months of therapy.21 However, in both cases the possibility exists that oral anticoagulation was inadvertently stopped and then restarted prior to the necrosis.
HISTOPATHOLOGY OF WARFARININDUCED SKIN NECROSIS From the Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma. Reprint requests: Dr. Comp, Oklahoma Memorial Hospital, EB-400, P.O. Box 26307, Oklahoma City, OK 73126.
The pathologic description of warfarin-induced skin necrosis has been based on relatively old skin lesions and little is known about the early histologic changes that occur before the onset of gross necrosis and tissue death. Early cases of skin necrosis were reported primarily by
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surgeons with little participation by pathologists. Although gross and microscopic findings were reported in many of these cases, surgical treatment of the necrotic lesions was the primary focus of the reports. Few skin lesions were biopsied and most tissue reports were generated from mastectomy specimens. These specimens were obtained after gangrenous demarcation had occurred and contained a mixture of primary changes and superimposed secondary changes, which included infection of the involved tissue. As a result, the pathologic impression of warfarin-induced skin necrosis has evolved over the past 5 decades to a point where it is a composite of circumstantial evidence. Specimens that are thought to reflect the early pathologic changes show microvascular injury with fibrin deposition in the postcapillary venules and small veins. These changes are presumed to cause the extensive cutaneous and subcutaneous infarction.22 Some specimens show acute inflammation with perivascular neutrophils and occasionally show lesions resembling vasculitis of the arteries or veins. 11,23 However, the majority of available data reveals microvascular thrombosis with fibrin deposition and little or no inflammation in the earliest lesions. 6,8,9,24,25 Skin lesions similar to those found in warfarininduced skin necrosis have been associated with: (1) homozygous protein C deficiency, (2) heparin administration in the presence or absence of thrombocytopenia, 26-33 (3) the purple toe or cholesterol embolization syndrome,33-39 (4) calciphylaxis,40,41 (5) pyoderma gangrenosum,42 (6) the lupus anticoagulant-associated skin necrosis, 25,43,44 and (7) cryofibrinogenemia.45 Several of these conditions are associated with an increased incidence of venous thrombosis (lupus anticoagulant) and may occur during warfarin therapy (purple toes syndrome and heparin-induced skin necrosis). These skin lesions are difficult, if not impossible, to distinguish from one another on histologic grounds. The clinical setting and cutaneous distribution may help in distinguishing these conditions.
FACTORS PREDISPOSING TO WARFARININDUCED SKIN NECROSIS The overwhelming majority of cases of warfarininduced skin necrosis occur in patients being treated for deep vein thrombosis or pulmonary emboli; typical examples can be found in both the medical and surgical literature. 14,16,46-51 Warfarin-induced skin necrosis can occur during the treatment of postoperative thrombophlebitis, 50,52,53 as well as during the treatment of patients who present to the hospital with thrombophlebitis or pulmonary emboli. While an association has been
drawn between warfarin-induced skin necrosis and cancer54,55 and other conditions,24 the common denominator is the presence of venous thrombosis. Rarely, warfarin-induced skin necrosis is reported in the setting of a major viral21 or bacterial56 infection or in the postoperative period in the absence of observed venous thrombosis.57 In marked contrast, patients placed on warfarin for cardiac indications, such as atrial fibrillation, or for cerebral vascular insufficiency rarely develop skin necrosis.47 The absence of warfarin-induced skin necrosis in patients placed on warfarin for arterial disease has also been noted.50 This suggests that the deep vein thrombosis and the warfarin-induced skin necrosis both may reflect an underlying hypercoagulable defect. Hypercoagulable conditions have indeed been detected in patients with warfarin-induced skin necrosis. Protein C deficiency has received particular attention 19,58-63 and hereditary protein C deficiency is considered a major risk factor for warfarin-induced skin necrosis. Skin necrosis has also been associated with acquired protein C deficiency.63-65 However, protein C deficiency is not the sole risk factor for warfarin-induced skin necrosis. Other hypercoagulable states have been identified in patients with skin necrosis; also patients with skin necrosis who have a normal protein C status have been identified. The three other hypercoagulable conditions that have been associated with warfarin-induced skin necrosis are antithrombin III deficiency,66 protein S deficiency, 67-69 and the lupus anticoagulant.68 Acquired abnormalities of protein C have been associated with warfarin-induced skin necrosis. 63-65 Evidence that warfarin-induced skin necrosis can occur in patients with normal protein C status can also be found. An analysis of 16 patients with a history of warfarin-induced skin necrosis revealed that only four had a type I deficiency of protein C and one had a type II deficiency.62 One documented case of warfarin-induced skin necrosis in a patient with normal protein C functional activity following the cessation of warfarin has been reported by Australian investigators.70 A third study involving 13 patients with a history of warfarin-induced skin necrosis revealed four patients with protein C antigen levels between 55 and 59% and five patients with protein C antigen between 60 and 100%.71 Protein C levels in these ranges are considered normal in many laboratories.
PROTEIN C AND SKIN NECROSIS Hereditary protein C deficiency is a risk factor for the development of warfarin-induced skin necrosis. However, type I heterozygous protein C deficiency is a
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relatively common inherited abnormality with a prevalence of 1 in 200 to 300 in the general population.72 This estimate did not include patients on chronic anticoagulant therapy and did not involve functional protein C determinations. Both these considerations suggest that the actual prevalence of protein C deficiency is even higher. If the administration of warfarin in the presence of protein C deficiency were the only requirement for the development of necrosis, warfarin-induced skin necrosis would be a common medical problem. Approximately 1,800,000 new warfarin prescriptions are written in the United States each year and, if the 10,000 or so protein C-deficient individuals anticipated to be in that population all developed skin necrosis, warfarin would have disappeared from the formulary long ago. This suggests that factors other than protein C deficiency alone determine which protein C-deficient patients receiving warfarin will develop skin necrosis. No matter what the cause of warfarin-induced skin necrosis, the differential effect of warfarin on protein C and vitamin K-dependent clotting factors early in the course of anticoagulant therapy may help trigger the microvascular thrombosis leading to skin necrosis. Protein C is a vitamin K-dependent plasma protein.73,74 Both protein C antigen and activity levels drop rapidly compared with vitamin K-dependent Factors IX, X and prothrombin following the initiation of warfarin.75,76 This observed rapid early fall in protein C prompted the hypothesis that the administration of warfarin to protein C-deficient individuals causes a temporary exaggeration of the imbalance between procoagulant and anticoagulant pathways, which leads to skin necrosis,59 that is, the protective effects of the anticoagulant protein C pathway are lost before the procoagulant pathways are inhibited. Transiently increased levels of prothrombin fragment 1 + 2, a marker of intravascular clotting,77 following the initiation of warfarin demonstrates that a transient hypercoagulable state may exist during the first 12 to 26 hours of warfarin administration.78 This transient imbalance of procoagulant and anticoagulant activity may be exaggerated in protein C-deficient individuals starting warfarin, since the baseline protein C level is low before therapy. However, no actual measurements are available comparing the magnitude of F1 + 2 elevation in protein C-deficient individuals and individuals normal in protein C. What determines which patients receiving warfarin will actually develop warfarin-induced skin necrosis is unknown. The fact that the necrosis occurs most frequently in patients with established deep vein thrombosis suggests that an underlying hypercoagulable state could be responsible for the development of both the deep vein thrombosis and the skin necrosis. This would not explain the finding that patients who have previously had warfarin-induced skin necrosis may not develop necrosis on
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subsequent exposure to warfarin.18,79 The possibility that the concomitant use of heparin in cases of deep vein thrombosis may predispose to warfarin-induced skin necrosis cannot be overlooked, especially when skin necrosis can be triggered by the use of heparin alone, as already discussed. Extensive deep vein thrombosis per se results in tissue damage and can potentially provoke a major inflammatory response in the body. This inflammation could result in a further shift in the hemostatic balance to favor thrombosis by bringing about down-regulation of the protein C pathway, decreased fibrinolytic activity, and increased tissue factor expression on cell surfaces;80 all these inflammation-mediated changes potentially predispose to microvascular thrombus formation and necrosis. The clinical pattern of anticoagulation in the setting of deep vein thrombosis is changing and both heparin and warfarin are now often started on the first day of hospital admission.81 This contrasts with the traditional practice of placing patients on heparin for 3 to 4 days before starting warfarin. If thrombophlebitis-induced inflammation plays a significant role in the etiology of warfarininduced skin necrosis, the incidence of necrosis may increase, since inflammatory effects may be more pronounced when the warfarin is first administered.
TREATMENT OF WARFARIN-INDUCED SKIN NECROSIS Warfarin-induced skin necrosis is a rare condition and no controlled studies concerning treatment exist. Termination of warfarin therapy is common when the diagnosis of warfarin-induced skin necrosis is made. Oral anticoagulation has been continued successfully in some cases,50 although medicolegal considerations may preclude this approach. Heparin and vitamin K have been administered acutely.14,53 The need for long-term anticoagulation in patients who have experienced recurrent thromboembolism remains a major consideration. Chronic administration of high doses of heparin can often prevent recurrence of deep vein thrombosis but is severely limited by the impracticality of frequent subcutaneous injection and the significant risk of osteoporosis. Oral anticoagulation has been successfully restarted following an initial episode of necrosis. 19,60,79,82 To reduce the risk of reoccurrence of necrosis, a very low initial dose of warfarin has been suggested under full intravenous heparinization well after the initial episode of venous thrombosis and skin necrosis have both resolved.9 The patient should be monitored carefully for recurrent necrosis. A protein C-deficient individual with a history of necrosis has been successfully anticoagulated with warfarin while receiving
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plasma and intravenous heparin.19 This suggests that supplementation with protein C during the initial stage of anticoagulation might offer some measure of protection. For patients with a history of necrosis and a deficiency of protein C, protein C concentrates may soon be available to provide normal levels of circulating protein C during the initial stages of anticoagulation.
PREVENTION OF SKIN NECROSIS The observation that deficiencies of protein C, protein S, and antithrombin III predispose to warfarininduced skin necrosis does not mandate that the levels of any or all of these natural anticoagulants be measured prior to initiating oral anticoagulant therapy. The rarity of skin necrosis and the fact that these tests would be neither particularly sensitive or specific in predicting risk of necrosis makes such an approach impractical. Also, withholding oral anticoagulation on the basis of these laboratory tests could prove a disservice to patients needing long-term treatment. Awareness by the physician of the very small possibility of skin necrosis in patients who are starting oral anticoagulation and familiarity with the early skin changes may possibly limit the extent of tissue damage by prompting early discontinuation of the drug.
CONCLUSIONS Warfarin-induced skin necrosis is a rare complication of oral anticoagulant therapy and concern regarding the possible occurrence of skin necrosis should not outweigh the vast body of clinical experience relating to the effectiveness of warfarin in preventing the recurrence of venous and arterial thrombosis. Warfarin-induced skin necrosis occurs most frequently during the initial treatment of deep vein thrombosis. The cutaneous distribution of the lesions and higher incidence in females is unexplained. Protein C deficiency and deficiencies of protein S and antithrombin III are risk factors, but necrosis can occur in individuals without demonstrable deficiencies of these natural anticoagulant proteins. The etiology of warfarin-induced skin necrosis may be multifactorial and acute inflammatory events may contribute to the development of thrombi in cutaneous vessels. The occurrence of a single episode of skin necrosis does not exclude the possible future reintroduction of oral anticoagulation in patients requiring long-term antithrombotic therapy.
REFERENCES 1. Chambers M, RD Thornes, M McKernan: Necrosis of skin induced by coumarin. Br Med J 298:755, 1989.
2. Marshall ME, K Butler, M Metcalfe, M Tate: Coumarin necrosis or Coumadin necrosis? Surgery 103:237-238, 1989. 3. Verhagen H: Local haemorrhage and necrosis of the skin and underlying tissues, during anti-coagulant therapy with dicumarol or dicumacyl. Acta Med Scand 148:453-462, 1954. 4. Nalbandian RM, IJ Mader, JL Barrett, JF Pearce, EC Rupp: A rare and striking dermatologic complication of coumarin congener anticoagulant therapy, including a note on effective treatment. Dermatol Digest 66:65-71, 1966. 5. Nalbandian RM, IJ Mader, JL Barrett, JF Peavee, EC Rupp: Petechiae, ecchymoses, and necrosis of skin induced by coumarin congeners. JAMA 192:107-112, 1965. 6. Renick AM: Anticoagulant-induced necrosis of skin and subcutaneous tissues: Report of two cases and review of the English literature. South Med J 69:775-804, 1976. 7. Koch-Weser J: Coumarin necrosis. Editorial notes. Ann Intern Med 68:1365-1367, 1968. 8. Cole MS, PK Minifee, FJ Wolma: Coumarin necrosis—a review of the literature. Surgery 103:271-277, 1988. 9. Horn JR, LH Danziger, RJ Davis: Warfarin-induced skin necrosis: Report of four cases. Am J Hosp Pharm 38:1763-1768, 1981. 10. Konrad P, L Mellblom, D Bergquist, B Holmberg, A Sjoberg: Coumarin associated skin necrosis. Vasa 17:208-215, 1988. 11. VonHaam E, JF Seidensticker, GE Hatfield: Coumarin-related breast necrosis: A case report and review of the literature. Ohio State Med J 70:38-42, 1974. 12. Kuntz HD, H Straub, B May: Coumarin necrosis at the upper leg. Muench Med Wochenschr 124:73, 1982. 13. Campbell R, TO Clanton, JD Heckman: Necrosis and gangrene as a complication of coumarin therapy. J Bone Joint Surg 62A: 1016— 1017, 1980. 14. Weinberg AC, G Lieskovsky, WG McGehee, DG Skinner: Warfarin necrosis of the skin and subcutaneous tissue of the male external genitalia. J Urol 130:352-354, 1983. 15. Vaughan ED, RA Moore, H Warren, DN Moler, JY Gillenwater: Skin necrosis of genitalia and warfarin therapy. JAMA 210:22822283, 1969. 16. Jordal R: Necrosing cutaneous haemorrhages as a complication in dicumarol treatment. Acta Med Scand 154:477-481, 1956. 17. Kandrotas RJ, J Deterding: Genital necrosis secondary to warfarin therapy. Pharmacotherapy 8:351-354, 1988. 18. Barkley C, RA Badalament, EN Metz, J Nesbitt, JR Drago: Coumarin necrosis of the penis. J Urol 141:946-948, 1989. 19. Zauber NP, MW Stark: Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis. Ann Intern Med 104:659-660, 1986. 20. Cameron ARE, W VanBerkel, JJ Sixma: Skin necrosis after three years of treatment with acenocoumarin. Ned Tijdschr Geneeskd 118:505-507, 1974. 21. Franson TR, HD Rose, MR Spivey, J Maroney, JA Libnoch: Late-onset warfarin-caused necrosis occurring in a patient with infectious mononucleosis. Arch Dermatol 120:927-931, 1984. 22. Faraci PA, RA Deterling, AM Stein, HF Rheinlander, RJ Cleveland: Warfarin induced necrosis of the skin. Surg Gynecol Obstet 146:695-700, 1978. 23. Martin BF, JD Phillips: Gangrene of the female breast with anticoagulant therapy: Report of two cases. Am J Clin Pathol 53:622-626, 1970. 24. Becker, CG. Oral anticoagulant therapy and skin necrosis: Speculations on pathogenesis. In: Wessler S, CG Becker, and Y Nemerson, Eds: The New Dimensions of Warfarin Prophylaxis, Plenum Press, New York, 1987, pp 217-222. 25. Alegre VA, RK Winkelmann: Histopathologic and immunofluorescence study of skin lesions associated with circulating lupus anticoagulant. J Am Acad Dermatol 19:117-124, 1988.
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26. Kelly RA, JA Gelfand, SH Pincus: Cutaneous necrosis caused by systemically administered heparin. JAMA 246:1582-1583, 1981. 27. Hartman AR, RM Hood, CE Anagnostopoulos: Phenomenon of heparin-induced thrombocytopenia associated with skin necrosis. J Vasc Surg 6:781-784, 1988. 28. Rongioletti F, S Pisani, M Ciaccio, A Rebora: Skin necrosis due to intravenous heparin. Dermatologica 178:47-50, 1989. 29. White PW, JR Sadd, RE Nelsel: Thrombotic complications of heparin therapy. Ann Surg 190:595-608, 1979. 30. Gold JA, AK Watters, E O'Brien: Coumadin versus heparin necrosis. J Am Acad Dermatol 16:148-150, 1987. 31. Hall JC, D McConahay, D Gibson: Heparin necrosis: An anticoagulation syndrome. JAMA 244:1831-1832, 1980. 32. Jackson AM, AV Pollock: Skin necrosis after heparin injection. Br Med J 283:1087-1088, 1981. 33. Levine LE, JE Bernstein, K Soltani, MM Medenica, CW Yung: Heparin-induced cutaneous necrosis unrelated to injection sites. A sign of potentially lethal complications. Arch Dermatol 119:400403, 1983. 34. Satinsky JD, IK Kline: The blue toe syndrome: Diagnostic and therapeutic considerations. Vasc Surg 15:279-286, 1981. 35. Feder W, R Auerbach: Purple toes: An uncommon sequela of oral coumarin drug therapy. Ann Intern Med 55:911-917, 1961. 36. DiCato MA: Purple toes syndrome: An uncommon complication of oral anticoagulant therapy. Postgrad Med 58:133-134, 1975. 37. Hyman BT, SK Landas, RF Ashman, RL Schelper, RA Robinson: Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med 82:1233-1237, 1987. 38. Fine MJ, W Kapoor, V Falanga: Cholesterol crystal embolization: A review of 221 cases in the English literature. Angiology 38:769-784, 1987. 39. Falanga V, MJ Fine, WN Kapoor: The cutaneous manifestations of cholesterol crystal embolization. Arch Dermatol 122:1194-1198, 1986. 40. Gipstein RM, JW Coburn, DA Adams, DBN Lee, KP Pasca, A Sellers, WN Suki, SG Massry: Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Arch Intern Med 136:1273-1280, 1976. 41. Grob JJ, R Legre, P Bertocchio, MJ Payan, L Andrac, JJ Bonerandi: Calcifying panniculitis and kidney failure. Considerations on pathogenesis and treatment of calciphylaxis. Int J Dermatol 28:129-131, 1989. 42. Goldgraber MB, JB Kirsner: Gangrenous skin lesions associated with chronic ulcerative colitis: A case study. Gastroenterology 39:94-103, 1960. 43. Grob JJ, JJ Bonerandi: Cutaneous manifestations associated with the presence of the lupus anticoagulant. J Am Acad Dermatol 15:211-219, 1986. 44. Dodd HJ, I Sarkany, D O'Shaughnessy: Widespread cutaneous necrosis associated with the lupus anticoagulant. Clin Exp Dermatol 10:581-586, 1985. 45. Rachmilewitz EA, MI Sacks, A Zlotnick: Essential cryofibrinogenemia: Clinical, pathological and immunological studies. Israel J Med Sci 6:32-43, 1970. 46. Desai SN: Extensive skin necrosis following anticoagulant therapy. Br J Plast Surg 20:325-331, 1967. 47. Schwartz M: Hemorrhagic cutaneous necrosis in dicumarol treatment. Nord Med 58:1260-1266, 1957. 48. Flood EP, MH Redish, SJ Bociek, S Shapiro: Thrombophlebitis migrans disseminata: Report of a case in which gangrene of a breast occurred. Coll Physicians Phil 11:2-5, 1986. 49. Groth O, B Tengstrom: Haemorrhagic necrosis of the skin during dicoumarol therapy. Acta Derm Venerol (Stockh) 40:104-107, 1960. 50. Nudelman HL, RL Kempson: Necrosis of the breast: A rare
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complication of anticoagulant therapy. Am J Surg 111:728-733, 1966. Lelek I, M Badics: Hemorrhagic skin-necrosis in the course of syncumar treatment. Orv Hetil 106:2242-2243, 1965. Diserens RV: Soft tissue hemorrhage and necrosis: An unusual reaction to coumarin therapy. Arix Med 30:775-777, 1973. Nalbandian RM, FK Beller, AK Kamp, RL Henry, PL Wolf: Coumarin necrosis of skin treated successfully with heparin. Obstet Gynecol 38:395-399, 1971. Korbitz BC, G Ramirez, S Mackman, H Davis: Coumarin-induced skin necrosis in a sixteen year old girl. Am J Cardiol 24:420-425, 1969. Everett RN, FL Jones: Warfarin-induced skin necrosis: A cutaneous sign of malignancy? Postgrad Med 79:97-103, 1986. Dominic W, JF Hansbrough, TO Field Jr, WB Carroll: Warfarininduced skin necrosis: An entity occasionally requiring burn wound expertise. Burns Incl Therm Inj 14:139-141, 1988. Caldwell EH, S Stewart: Skin necrosis as a consequence of Coumadin therapy. Plast Reconstr Surg 72:231-233, 1983. Broekmans AW, RM Bertina, EA Loeliger, V Hofmann, HG Klingemann: Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 49:251, 1983. McGehee WG, T Klotz, DJ Epstein, SI Rapaport: Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med 100:59-60, 1984. Samama M, MH Horellou, J Soria, J Conard, G Nicolas: Successful progressive anticoagulation in a severe protein C deficiency and previous skin necrosis at the initiation of oral anticoagulant treatment. Thromb Haemost 51:132-133, 1984. Rose VL, HC Kwaan, K Williamson, D Hoppensteadt, J Walenga, J Fareed: Protein C antigen deficiency and warfarin necrosis. Am J Clin Pathol 86:653-655, 1986. Broekmans AW, RBC Teepe, FJM van der Meer, E Briet, RM Bertina: Protein C and coumarin induced skin necrosis. Thromb Res Suppl VI:137, 1987. Conlan MG, A Bridges, E Williams, R Marlar: Familial type II protein C deficiency associated with warfarin-induced skin necrosis and bilateral adrenal hemorrhage. Am J Hematol 29:226-229, 1988. Gruber A, G Blasko, G Sas: Functional deficiency of protein C and skin necrosis in multiple myeloma. Thromb Res 42:579-581, 1986. Teepe RBC, AW Broekmans, BJ Vermeer, AM Nienhuis, EA Loeliger: Recurrent coumarin-induced skin necrosis in a patient with an acquired functional protein C deficiency. Arch Dermatol 122:1408-1412, 1986. Kiehl R, P Hellstern, E Wenzel: Hereditary antithrombin III deficiency and atypical localization of a coumarin necrosis. Thromb Res 45:191-193, 1987. Grimaudo V, F Gueissaz, J Hauert, A Sarraj, EKO Kruithof, F Bachmann: Necrosis of skin induced by coumarin in a patient deficient in protein S. Br Med J 298:233-234, 1989. Moreb J, CS Kitchens: Acquired functional protein S deficiency, cerebral venous thrombosis, and coumarin skin necrosis in association with antiphospholipid syndrome: Report of two cases. Am J Med 87:207-210, 1989. Friedman KD, R Marlar, JG Houston, RR Montgomery: Warfarininduced skin necrosis in a patient with protein S deficiency. (Abst.) Blood 68:333, 1986. Rowbotham B, W Clouston, N Kime, J Rowell, T Exner: Coumarin skin necrosis without protein C deficiency. (Letter.) AustNZJMed 16:513, 1986. Hofmann V, PG Frick: Repeated occurrence of skin necrosis twice following coumarin intake and subsequently during decrease of
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Warfarin-Induced Skin Necrosis
Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This review will discuss the clinical presentation, natural history, incidence, and possible etiologies of this condition as well as the limited therapeutic options available to the clinician. The term "warfarin-induced skin necrosis" will be used throughout this review although similar necrotic skin lesions have been observed following a variety of other oral anticoagulant compounds. Although the term "coumarin-induced skin necrosis" is found in the medical literature, it is probably less suitable. Coumarin is the parent compound from which many oral anticoagulants, including warfarin, are derived. However, coumarin itself has no anticoagulant activity and is not used clinically for that purpose.1'2
CLINICAL PRESENTATION Warfarin-induced skin necrosis presents as a discolored area of skin that often progresses to frank necrosis of the skin and the underlying fatty tissue. The clinical presentation of warfarin-induced skin necrosis has been described in over 300 articles and case reports over the last 35 years3-5 and has been the subject of several comprehensive reviews. 6-10 Warfarin-induced skin necrosis may initially present as a painful area of skin on the third to sixth day following the initiation of oral anticoagulation. The skin has been described as "erythematous," "flushed," or "darkened," and the patient may complain of a sensation of pressure in the affected area.
Petechial hemorrhages may next appear in the skin with sharp demarcation of the borders. Hemorrhagic bullae may be present at this stage. The affected skin then becomes necrotic and blackened and eschar appears. The necrotic skin may separate from the underlying tissues. The resulting wound is frequently repaired surgically or may be allowed to heal spontaneously. The diagnosis of warfarin-induced skin necrosis is complicated by the frequent occurrence of subcutaneous hemorrhage in patients on oral anticoagulants. Hemorrhagic complications are not particularly common early in the course of oral anticoagulation and do not result in necrosis of the skin or underlying tissue. Warfarin-induced skin necrosis occurs more frequently in females (over 75% of cases). The breasts appear to be most frequently affected,11 followed by the thighs,12 buttocks, and occasionally the legs.13 The distribution in men is similar with sparing of the breasts; necrosis of the penis has been reported. 3,14-19 No convincing arguments have been advanced to explain the apparent predilection for areas, such as the breasts, with underlying fatty tissue. The majority of lesions occur between the third and sixth day of oral anticoagulant therapy. In one patient, skin necrosis occurred 3 years after the initiation of an oral anticoagulant20 and in another case after 17 months of therapy.21 However, in both cases the possibility exists that oral anticoagulation was inadvertently stopped and then restarted prior to the necrosis.
HISTOPATHOLOGY OF WARFARININDUCED SKIN NECROSIS From the Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma. Reprint requests: Dr. Comp, Oklahoma Memorial Hospital, EB-400, P.O. Box 26307, Oklahoma City, OK 73126.
The pathologic description of warfarin-induced skin necrosis has been based on relatively old skin lesions and little is known about the early histologic changes that occur before the onset of gross necrosis and tissue death. Early cases of skin necrosis were reported primarily by
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PHILIP C. COMP, M.D., Ph.D., JAMES P. ELROD, M.D., and STACEY KARZENSKI
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surgeons with little participation by pathologists. Although gross and microscopic findings were reported in many of these cases, surgical treatment of the necrotic lesions was the primary focus of the reports. Few skin lesions were biopsied and most tissue reports were generated from mastectomy specimens. These specimens were obtained after gangrenous demarcation had occurred and contained a mixture of primary changes and superimposed secondary changes, which included infection of the involved tissue. As a result, the pathologic impression of warfarin-induced skin necrosis has evolved over the past 5 decades to a point where it is a composite of circumstantial evidence. Specimens that are thought to reflect the early pathologic changes show microvascular injury with fibrin deposition in the postcapillary venules and small veins. These changes are presumed to cause the extensive cutaneous and subcutaneous infarction.22 Some specimens show acute inflammation with perivascular neutrophils and occasionally show lesions resembling vasculitis of the arteries or veins. 11,23 However, the majority of available data reveals microvascular thrombosis with fibrin deposition and little or no inflammation in the earliest lesions. 6,8,9,24,25 Skin lesions similar to those found in warfarininduced skin necrosis have been associated with: (1) homozygous protein C deficiency, (2) heparin administration in the presence or absence of thrombocytopenia, 26-33 (3) the purple toe or cholesterol embolization syndrome,33-39 (4) calciphylaxis,40,41 (5) pyoderma gangrenosum,42 (6) the lupus anticoagulant-associated skin necrosis, 25,43,44 and (7) cryofibrinogenemia.45 Several of these conditions are associated with an increased incidence of venous thrombosis (lupus anticoagulant) and may occur during warfarin therapy (purple toes syndrome and heparin-induced skin necrosis). These skin lesions are difficult, if not impossible, to distinguish from one another on histologic grounds. The clinical setting and cutaneous distribution may help in distinguishing these conditions.
FACTORS PREDISPOSING TO WARFARININDUCED SKIN NECROSIS The overwhelming majority of cases of warfarininduced skin necrosis occur in patients being treated for deep vein thrombosis or pulmonary emboli; typical examples can be found in both the medical and surgical literature. 14,16,46-51 Warfarin-induced skin necrosis can occur during the treatment of postoperative thrombophlebitis, 50,52,53 as well as during the treatment of patients who present to the hospital with thrombophlebitis or pulmonary emboli. While an association has been
drawn between warfarin-induced skin necrosis and cancer54,55 and other conditions,24 the common denominator is the presence of venous thrombosis. Rarely, warfarin-induced skin necrosis is reported in the setting of a major viral21 or bacterial56 infection or in the postoperative period in the absence of observed venous thrombosis.57 In marked contrast, patients placed on warfarin for cardiac indications, such as atrial fibrillation, or for cerebral vascular insufficiency rarely develop skin necrosis.47 The absence of warfarin-induced skin necrosis in patients placed on warfarin for arterial disease has also been noted.50 This suggests that the deep vein thrombosis and the warfarin-induced skin necrosis both may reflect an underlying hypercoagulable defect. Hypercoagulable conditions have indeed been detected in patients with warfarin-induced skin necrosis. Protein C deficiency has received particular attention 19,58-63 and hereditary protein C deficiency is considered a major risk factor for warfarin-induced skin necrosis. Skin necrosis has also been associated with acquired protein C deficiency.63-65 However, protein C deficiency is not the sole risk factor for warfarin-induced skin necrosis. Other hypercoagulable states have been identified in patients with skin necrosis; also patients with skin necrosis who have a normal protein C status have been identified. The three other hypercoagulable conditions that have been associated with warfarin-induced skin necrosis are antithrombin III deficiency,66 protein S deficiency, 67-69 and the lupus anticoagulant.68 Acquired abnormalities of protein C have been associated with warfarin-induced skin necrosis. 63-65 Evidence that warfarin-induced skin necrosis can occur in patients with normal protein C status can also be found. An analysis of 16 patients with a history of warfarin-induced skin necrosis revealed that only four had a type I deficiency of protein C and one had a type II deficiency.62 One documented case of warfarin-induced skin necrosis in a patient with normal protein C functional activity following the cessation of warfarin has been reported by Australian investigators.70 A third study involving 13 patients with a history of warfarin-induced skin necrosis revealed four patients with protein C antigen levels between 55 and 59% and five patients with protein C antigen between 60 and 100%.71 Protein C levels in these ranges are considered normal in many laboratories.
PROTEIN C AND SKIN NECROSIS Hereditary protein C deficiency is a risk factor for the development of warfarin-induced skin necrosis. However, type I heterozygous protein C deficiency is a
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relatively common inherited abnormality with a prevalence of 1 in 200 to 300 in the general population.72 This estimate did not include patients on chronic anticoagulant therapy and did not involve functional protein C determinations. Both these considerations suggest that the actual prevalence of protein C deficiency is even higher. If the administration of warfarin in the presence of protein C deficiency were the only requirement for the development of necrosis, warfarin-induced skin necrosis would be a common medical problem. Approximately 1,800,000 new warfarin prescriptions are written in the United States each year and, if the 10,000 or so protein C-deficient individuals anticipated to be in that population all developed skin necrosis, warfarin would have disappeared from the formulary long ago. This suggests that factors other than protein C deficiency alone determine which protein C-deficient patients receiving warfarin will develop skin necrosis. No matter what the cause of warfarin-induced skin necrosis, the differential effect of warfarin on protein C and vitamin K-dependent clotting factors early in the course of anticoagulant therapy may help trigger the microvascular thrombosis leading to skin necrosis. Protein C is a vitamin K-dependent plasma protein.73,74 Both protein C antigen and activity levels drop rapidly compared with vitamin K-dependent Factors IX, X and prothrombin following the initiation of warfarin.75,76 This observed rapid early fall in protein C prompted the hypothesis that the administration of warfarin to protein C-deficient individuals causes a temporary exaggeration of the imbalance between procoagulant and anticoagulant pathways, which leads to skin necrosis,59 that is, the protective effects of the anticoagulant protein C pathway are lost before the procoagulant pathways are inhibited. Transiently increased levels of prothrombin fragment 1 + 2, a marker of intravascular clotting,77 following the initiation of warfarin demonstrates that a transient hypercoagulable state may exist during the first 12 to 26 hours of warfarin administration.78 This transient imbalance of procoagulant and anticoagulant activity may be exaggerated in protein C-deficient individuals starting warfarin, since the baseline protein C level is low before therapy. However, no actual measurements are available comparing the magnitude of F1 + 2 elevation in protein C-deficient individuals and individuals normal in protein C. What determines which patients receiving warfarin will actually develop warfarin-induced skin necrosis is unknown. The fact that the necrosis occurs most frequently in patients with established deep vein thrombosis suggests that an underlying hypercoagulable state could be responsible for the development of both the deep vein thrombosis and the skin necrosis. This would not explain the finding that patients who have previously had warfarin-induced skin necrosis may not develop necrosis on
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subsequent exposure to warfarin.18,79 The possibility that the concomitant use of heparin in cases of deep vein thrombosis may predispose to warfarin-induced skin necrosis cannot be overlooked, especially when skin necrosis can be triggered by the use of heparin alone, as already discussed. Extensive deep vein thrombosis per se results in tissue damage and can potentially provoke a major inflammatory response in the body. This inflammation could result in a further shift in the hemostatic balance to favor thrombosis by bringing about down-regulation of the protein C pathway, decreased fibrinolytic activity, and increased tissue factor expression on cell surfaces;80 all these inflammation-mediated changes potentially predispose to microvascular thrombus formation and necrosis. The clinical pattern of anticoagulation in the setting of deep vein thrombosis is changing and both heparin and warfarin are now often started on the first day of hospital admission.81 This contrasts with the traditional practice of placing patients on heparin for 3 to 4 days before starting warfarin. If thrombophlebitis-induced inflammation plays a significant role in the etiology of warfarininduced skin necrosis, the incidence of necrosis may increase, since inflammatory effects may be more pronounced when the warfarin is first administered.
TREATMENT OF WARFARIN-INDUCED SKIN NECROSIS Warfarin-induced skin necrosis is a rare condition and no controlled studies concerning treatment exist. Termination of warfarin therapy is common when the diagnosis of warfarin-induced skin necrosis is made. Oral anticoagulation has been continued successfully in some cases,50 although medicolegal considerations may preclude this approach. Heparin and vitamin K have been administered acutely.14,53 The need for long-term anticoagulation in patients who have experienced recurrent thromboembolism remains a major consideration. Chronic administration of high doses of heparin can often prevent recurrence of deep vein thrombosis but is severely limited by the impracticality of frequent subcutaneous injection and the significant risk of osteoporosis. Oral anticoagulation has been successfully restarted following an initial episode of necrosis. 19,60,79,82 To reduce the risk of reoccurrence of necrosis, a very low initial dose of warfarin has been suggested under full intravenous heparinization well after the initial episode of venous thrombosis and skin necrosis have both resolved.9 The patient should be monitored carefully for recurrent necrosis. A protein C-deficient individual with a history of necrosis has been successfully anticoagulated with warfarin while receiving
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plasma and intravenous heparin.19 This suggests that supplementation with protein C during the initial stage of anticoagulation might offer some measure of protection. For patients with a history of necrosis and a deficiency of protein C, protein C concentrates may soon be available to provide normal levels of circulating protein C during the initial stages of anticoagulation.
PREVENTION OF SKIN NECROSIS The observation that deficiencies of protein C, protein S, and antithrombin III predispose to warfarininduced skin necrosis does not mandate that the levels of any or all of these natural anticoagulants be measured prior to initiating oral anticoagulant therapy. The rarity of skin necrosis and the fact that these tests would be neither particularly sensitive or specific in predicting risk of necrosis makes such an approach impractical. Also, withholding oral anticoagulation on the basis of these laboratory tests could prove a disservice to patients needing long-term treatment. Awareness by the physician of the very small possibility of skin necrosis in patients who are starting oral anticoagulation and familiarity with the early skin changes may possibly limit the extent of tissue damage by prompting early discontinuation of the drug.
CONCLUSIONS Warfarin-induced skin necrosis is a rare complication of oral anticoagulant therapy and concern regarding the possible occurrence of skin necrosis should not outweigh the vast body of clinical experience relating to the effectiveness of warfarin in preventing the recurrence of venous and arterial thrombosis. Warfarin-induced skin necrosis occurs most frequently during the initial treatment of deep vein thrombosis. The cutaneous distribution of the lesions and higher incidence in females is unexplained. Protein C deficiency and deficiencies of protein S and antithrombin III are risk factors, but necrosis can occur in individuals without demonstrable deficiencies of these natural anticoagulant proteins. The etiology of warfarin-induced skin necrosis may be multifactorial and acute inflammatory events may contribute to the development of thrombi in cutaneous vessels. The occurrence of a single episode of skin necrosis does not exclude the possible future reintroduction of oral anticoagulation in patients requiring long-term antithrombotic therapy.
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