British Journal of Dermatology (1976) 94, 97.
Skin necrosis following warfarin therapy JOHN D.KIRBY AND PHILIP J.MARRIOTT Deparlment of Dermatology, St Bartholomew's Hospital, London ECiA 7BE
Accepted for publication 14 May 1975
SUMMARY
A typical case of skin necrosis following anticoagulant therapy with warfarin is described.
Skin necrosis following coumarin anticoagulant therapy is a rare complication. Reports from Europe and the United States show that it is seen in those countries. The literature contains no British reference. We wish to record this hazard following the use of warfarin sodium. The patient, a 52-year-oId woman, in March 1974 had been prescribed warfarin for 7 weeks following thrombophlebitis in the left leg. In July 1974 she was readmitted with a diagnosis of venoocclusive disease and pulmonary emboli. Anticoagulant therapy was started with heparin and warfarin sodium. Her course during her second admission was as follows: Day I. Heparin 20,000 units 12 hourly was given intravenously and warfarin sodium 40 mg orally.
FIGURE I. Full extent of skin and subcutaneous tissue loss from the right buttock after debridement.
97
98
J.D.Kirby and P.JMarnott
Fifteen minutes after receiving warfarin she vomited and a repeat dose of 40 mg was given. Day 4. Her prothrombin time was 44 s. She complained of painful hips, and discoloration of the skin resembling early bruising was noticed. Day 5. The skin over both hips had developed a livid purple discoloration. The prothrombin time was 55 s (control 15 s). 20 mg vitamin K was given intravenously. Day 6. Hacmorrhagic blisters appeared over the discoloured skin on both thighs, and they became more extensive on her body during the next 24 h. Erythema and induration had appeared surrounding the infarcted skin. There was no evidence elsewhere of purpura or ecchymoses. In the next 10 days the area of necrosis formed an eschar and began to separate from the subcutaneous tissue. The area became purulent; the patient developed a pyrexia and Siaph. aureus was isolated from the right thigh. The necrotic skin was removed from the right hip following increasing pain and a continuing pyrexia. Extensive necrosis of fat with abscess formation was noted by the surgeon, who the next day removed all necrotic debris from the wound. Two attempts were made to graft areas of the large wound with split skin from the left thigh. On both occasions the graft sloughed. The wound was treated daily by simple toilet and has re-epitheliahzed after 4 months. COMMENT
This patient developed extensive skin necrosis 4 days after receiving warfarin sodium on the second occasion for veno-occlusive disease. The area of tissue loss was large and extended deep into subcutaneous fat. Bacterial infection has been difficult to eradicate, and pain to control. Nursing has been a cumbersome task. Since Verhagen & Wiersema (1952) and Verhagen (1954) reviewed this rare complication following coumarin anticoagulant therapy, further reports have followed in the European and American literature. There are more than 150 cases reported (Everitt & Overholt, 1969), but there are no references to it in the British literature. No report has been made to the Committee on the Safety of Medicines (personal communication). The majority of cases have occurred in obese middle-aged women, the lesions having a predilection for fatty areas such as thighs, buttocks, abdomen and breasts. An evanescent erythema coinciding with pain in the area affected is the first indication of the condition. In 90",, of patients the complication is seen between the 3rd and 6th day of treatment. Our patient's course, progressing from erythema to purple ecchymotic changes, blistering and necrosis is typical of cases so far reported. The indications for anticoagulant therapy in the patients reviewed by Verhagen (1954) and the cases described by Nalbandian et al. (1965) reveal no common underlying pathology. Reports on the incidence of cutaneous necrosis amongst the various coumarins suggest it is less common with warfarin than with bishydroxyeoumarin (Dicoumarol) and other coumarins (Nalbandian et al., 1965). This may reflect the varying usage of different anticoagulants in America and Europe. In 1973 289,000 G.P. prescriptions for warfarin sodium were issued in the U.K. It is now the market leader amongst anticoagulants. Sales of warfarin in the U.S.A. are approximately double our own, and in Erance and Germany are approximately half those in the U.K. Noteworthy in this case and also in one reported by Nalbandian (1964) is the occurrence with the use of a coumarin for the second time. Although in most reported cases the drug has been stopped, its continuation is said not to exacerbate the condition or delay skin healing (Nalbandian et al, 1965; Verhagen, 1954; Hague, 1957; Epiney, 1963). Examples have been reported with repeated use of the same coumarin failing to cause necrosis a second time and variable response in the same patient to different coumarins (Nalbandian et al., 1965). Scarification and intracutaneous skin challenge produce
Skin necrosis following warfarin therapy
99
no reaction (Stafanelli a al.^ i960). Such evidence would seem to preclude a hypersensitivity reaction. No histology is available from our patient but reports in the literature suggest selective involvement of skin capillaries and venules with thrombi; later haemorrhage and finally fat necrosis occur (Flood et al., 1943; Sailer & Wayner, i960; Epiney, 1963). Endothelial proliferation and hyaline necrosis of the walls of small vessels occurred as a generalized change in dogs given toxic doses of dicoumarol (McCarter, Bingham & Meyer, 1944). The site of the initial lesions is purported to be the junction of the dermovascular capillary loop with the precapillary arteriole (Nalbandian et al., 1965). The evolution of clinical changes would fit this theory, and skin petcchiae arise from this site (Humble, 1949). There is no definitive treatment described. The onset of the complication is not related to prolongation of the prothrombin time or depression of clotting factors. Early administration of heparin might be expected to inhibit thrombosis, and Beller (1961) claimed benefit with this treatment, although others have been unsuccessful with its use. REFERENCES BELLER, F . K . (1961) Therapy of so-called Coumarin necrosis. Abstract. Medicine el Biologie (Paris), 4, 116. EPINEY, J. (1963) Necrosecutan^eet anticoagulants. Revue Medicatede la SuisseRomaiide, 83, roil. EVERETT, E.D., OVEKHOLT, E . L . (1969) Haemorrhagic skin infarction secondary to oral anticoagulants. Archives of Dermatology, ioo, 588. FLOOD, E.P., REDISH, M.H., BOCIEK, S J . & SHAPIRO, S. (1943) Thrombophlebitis migrans disseminata: report of
a case in which gangrene of the breast occurred. New York State Journal of Medicine, 43, 1121. HAGUE, J. (1957) Haemorrhagisk Hudnekrose ved Dicumarolbehandlung. Nordiskt Medicinskr Arkiv, 58, 1266. HUMBLE, J.G. (1949) Mechanism of petechial haemorrhage formation. Blood, 4, 69. MCCARTER, J.C., BINGHAM, J.B. & MEYER, O.O. (1944) Studies on haemorrhagic agent 3.3' Methylenebis (4 Hydroxycoumarin). American Journal of Pathology, 20, 65 r. NALBANDIAN, R.M., MADER, I.J., BARRETT, J.L., PEARCE, J . F . & RUPP, B.C. (1965) Petechiaej ecchymoses and
necrosis of skin induced by coumarin congeners. Journal of the American Medical Association, 192, 107. SAILER, S. & WAGNER, K . (i960) Thrombosen unter der Behandlung mit Antikoagulaniien. Wiener Klinische Wochenschrift, 72, 152. STAFANELLI, N . , TULZER, H . & WEWALKA, F . (i960) Hautnekrosen als Nebenwirkung der Therapie mit Antikoagulantien. Thrombosis et Diathesis Haemorrhagica, 5, 136. VERHAGEN, H . (1954) Local haemorrhage and necrosis of skin and underlying tissues during anticoagulant therapy with Dicoumarol or Dicumacyl. Acta Medica Scandinavica, 148,453. VERHAGEN, H . & WIERSEMA, M . U . (1952) Huidbloeding en Necrose bij Patienten met Thrombose behandeld met Dicumol af Dicumacyl. Nederlandsch tijdshrift voorgeneeskunde, 96, 1578.
Skin necrosis following warfarin therapy JOHN D.KIRBY AND PHILIP J.MARRIOTT Deparlment of Dermatology, St Bartholomew's Hospital, London ECiA 7BE
Accepted for publication 14 May 1975
SUMMARY
A typical case of skin necrosis following anticoagulant therapy with warfarin is described.
Skin necrosis following coumarin anticoagulant therapy is a rare complication. Reports from Europe and the United States show that it is seen in those countries. The literature contains no British reference. We wish to record this hazard following the use of warfarin sodium. The patient, a 52-year-oId woman, in March 1974 had been prescribed warfarin for 7 weeks following thrombophlebitis in the left leg. In July 1974 she was readmitted with a diagnosis of venoocclusive disease and pulmonary emboli. Anticoagulant therapy was started with heparin and warfarin sodium. Her course during her second admission was as follows: Day I. Heparin 20,000 units 12 hourly was given intravenously and warfarin sodium 40 mg orally.
FIGURE I. Full extent of skin and subcutaneous tissue loss from the right buttock after debridement.
97
98
J.D.Kirby and P.JMarnott
Fifteen minutes after receiving warfarin she vomited and a repeat dose of 40 mg was given. Day 4. Her prothrombin time was 44 s. She complained of painful hips, and discoloration of the skin resembling early bruising was noticed. Day 5. The skin over both hips had developed a livid purple discoloration. The prothrombin time was 55 s (control 15 s). 20 mg vitamin K was given intravenously. Day 6. Hacmorrhagic blisters appeared over the discoloured skin on both thighs, and they became more extensive on her body during the next 24 h. Erythema and induration had appeared surrounding the infarcted skin. There was no evidence elsewhere of purpura or ecchymoses. In the next 10 days the area of necrosis formed an eschar and began to separate from the subcutaneous tissue. The area became purulent; the patient developed a pyrexia and Siaph. aureus was isolated from the right thigh. The necrotic skin was removed from the right hip following increasing pain and a continuing pyrexia. Extensive necrosis of fat with abscess formation was noted by the surgeon, who the next day removed all necrotic debris from the wound. Two attempts were made to graft areas of the large wound with split skin from the left thigh. On both occasions the graft sloughed. The wound was treated daily by simple toilet and has re-epitheliahzed after 4 months. COMMENT
This patient developed extensive skin necrosis 4 days after receiving warfarin sodium on the second occasion for veno-occlusive disease. The area of tissue loss was large and extended deep into subcutaneous fat. Bacterial infection has been difficult to eradicate, and pain to control. Nursing has been a cumbersome task. Since Verhagen & Wiersema (1952) and Verhagen (1954) reviewed this rare complication following coumarin anticoagulant therapy, further reports have followed in the European and American literature. There are more than 150 cases reported (Everitt & Overholt, 1969), but there are no references to it in the British literature. No report has been made to the Committee on the Safety of Medicines (personal communication). The majority of cases have occurred in obese middle-aged women, the lesions having a predilection for fatty areas such as thighs, buttocks, abdomen and breasts. An evanescent erythema coinciding with pain in the area affected is the first indication of the condition. In 90",, of patients the complication is seen between the 3rd and 6th day of treatment. Our patient's course, progressing from erythema to purple ecchymotic changes, blistering and necrosis is typical of cases so far reported. The indications for anticoagulant therapy in the patients reviewed by Verhagen (1954) and the cases described by Nalbandian et al. (1965) reveal no common underlying pathology. Reports on the incidence of cutaneous necrosis amongst the various coumarins suggest it is less common with warfarin than with bishydroxyeoumarin (Dicoumarol) and other coumarins (Nalbandian et al., 1965). This may reflect the varying usage of different anticoagulants in America and Europe. In 1973 289,000 G.P. prescriptions for warfarin sodium were issued in the U.K. It is now the market leader amongst anticoagulants. Sales of warfarin in the U.S.A. are approximately double our own, and in Erance and Germany are approximately half those in the U.K. Noteworthy in this case and also in one reported by Nalbandian (1964) is the occurrence with the use of a coumarin for the second time. Although in most reported cases the drug has been stopped, its continuation is said not to exacerbate the condition or delay skin healing (Nalbandian et al, 1965; Verhagen, 1954; Hague, 1957; Epiney, 1963). Examples have been reported with repeated use of the same coumarin failing to cause necrosis a second time and variable response in the same patient to different coumarins (Nalbandian et al., 1965). Scarification and intracutaneous skin challenge produce
Skin necrosis following warfarin therapy
99
no reaction (Stafanelli a al.^ i960). Such evidence would seem to preclude a hypersensitivity reaction. No histology is available from our patient but reports in the literature suggest selective involvement of skin capillaries and venules with thrombi; later haemorrhage and finally fat necrosis occur (Flood et al., 1943; Sailer & Wayner, i960; Epiney, 1963). Endothelial proliferation and hyaline necrosis of the walls of small vessels occurred as a generalized change in dogs given toxic doses of dicoumarol (McCarter, Bingham & Meyer, 1944). The site of the initial lesions is purported to be the junction of the dermovascular capillary loop with the precapillary arteriole (Nalbandian et al., 1965). The evolution of clinical changes would fit this theory, and skin petcchiae arise from this site (Humble, 1949). There is no definitive treatment described. The onset of the complication is not related to prolongation of the prothrombin time or depression of clotting factors. Early administration of heparin might be expected to inhibit thrombosis, and Beller (1961) claimed benefit with this treatment, although others have been unsuccessful with its use. REFERENCES BELLER, F . K . (1961) Therapy of so-called Coumarin necrosis. Abstract. Medicine el Biologie (Paris), 4, 116. EPINEY, J. (1963) Necrosecutan^eet anticoagulants. Revue Medicatede la SuisseRomaiide, 83, roil. EVERETT, E.D., OVEKHOLT, E . L . (1969) Haemorrhagic skin infarction secondary to oral anticoagulants. Archives of Dermatology, ioo, 588. FLOOD, E.P., REDISH, M.H., BOCIEK, S J . & SHAPIRO, S. (1943) Thrombophlebitis migrans disseminata: report of
a case in which gangrene of the breast occurred. New York State Journal of Medicine, 43, 1121. HAGUE, J. (1957) Haemorrhagisk Hudnekrose ved Dicumarolbehandlung. Nordiskt Medicinskr Arkiv, 58, 1266. HUMBLE, J.G. (1949) Mechanism of petechial haemorrhage formation. Blood, 4, 69. MCCARTER, J.C., BINGHAM, J.B. & MEYER, O.O. (1944) Studies on haemorrhagic agent 3.3' Methylenebis (4 Hydroxycoumarin). American Journal of Pathology, 20, 65 r. NALBANDIAN, R.M., MADER, I.J., BARRETT, J.L., PEARCE, J . F . & RUPP, B.C. (1965) Petechiaej ecchymoses and
necrosis of skin induced by coumarin congeners. Journal of the American Medical Association, 192, 107. SAILER, S. & WAGNER, K . (i960) Thrombosen unter der Behandlung mit Antikoagulaniien. Wiener Klinische Wochenschrift, 72, 152. STAFANELLI, N . , TULZER, H . & WEWALKA, F . (i960) Hautnekrosen als Nebenwirkung der Therapie mit Antikoagulantien. Thrombosis et Diathesis Haemorrhagica, 5, 136. VERHAGEN, H . (1954) Local haemorrhage and necrosis of skin and underlying tissues during anticoagulant therapy with Dicoumarol or Dicumacyl. Acta Medica Scandinavica, 148,453. VERHAGEN, H . & WIERSEMA, M . U . (1952) Huidbloeding en Necrose bij Patienten met Thrombose behandeld met Dicumol af Dicumacyl. Nederlandsch tijdshrift voorgeneeskunde, 96, 1578.
