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Fatal warfarin-induced skin necrosis after total hip arthroplasty
The Journal of Arthroplasty Vol. 17 No. 8 2002
Case Report
Fatal Warfarin-Induced Skin Necrosis After Total Hip Arthroplasty Jeffrey A. Clark, DO,* and Barron R. B. Bremner, D o t
Abstract: Skin necrosis associated with warfarin anticoagulation is a rare but serious complication. Few cases of warfarin-induced skin necrosis are found in the orthopaedic literature. We report a fatal case of warfarin-induced skin necrosis after total hip arthroplasty. Key words: total hip arthroplasty (THA), warfarin, fatal skin necrosis. Copyright 2002, Elsevier Science (USA). All rights reserved.
Skin necrosis associated with warfarin is rare. The complication is of sudden onset and can cause significant morbidity and is potentially lethal [ 11. We report a case of extensive skin necrosis over the buttocks and lower extremities after total hip arthroplasty (THA) that resulted in the death of the patient. To our knowledge, warfarin-induced skin necrosis has been reported only once in the orthopaedic literature [2]. Recognizing the complications of warfarin anticoagulation therapy requires a n appropriate index of suspicion in the proper clinical setting.
Case Report A 70-year-old white woman had a right THA for degenerative joint disease done on June 22, 1998. From the *Department of Orthopaedics, Michigan State University, Garden City Hospital, Garden City, Michigan; and fosteopathic Medical Center, Des Moines University, Des Moines, Iowa. Submitted September 28, 2001; accepted April 10, 2002. No benefits or funds were received in support of this study. Reprint requests: Barron R. B. Bremner, DO, 819 48th Aven u e N W , Rochester, MN 55901. E-mail: bremner.barron@ mayo .edu Copyright 2002, Elsevier Science (USA).All rights reserved. 0883-5403/02/1708-0029$35.00/0 doi:10.1054/a1th.2002.34816
Significant medical history included hypertension, hypercholesterolemia, obesity, and right breast cancer with lumpectomy and radiation. There was no history of stroke, deep venous thrombosis, or other thromboembolic events. Medications on admission included fosinopril, simvastatin, iron sulfate, hydrocodone, and tamoxifen. There was no previous history of warfarin therapy. Results of coagulation studies, thyroid function tests, urinalysis, and other laboratory data were unremarkable. One day before the THA, the patient was given a 5.0-mg dose of warfarin. No complications were reported during the operation. Postoperatively, warfarin dosing was adjusted to achieve a desired international normalized ratio (INR) between 2.0 and 3.0 for a total of 21 days after surgery. The patient was discharged on postoperative day 5 with no reported complications. Office follow-up visits were routine, and the patient was reporting minimal pain and ambulating independently. O n August 11, 1998, during a scheduled office follow-up, the patient complained of right leg swelling and pain. Referral to the emergency department was made, and a n ultrasound study revealed extensive thrombi in the proximal vessels of the right lower extremity. Intravenous
1070
Fatal Warfarin-Induced Skin Necrosis After THA
Clark and Bremner
1071
Pig. 1. Photograph of the right lateral thigh. (Courtesy of Marshall A. Shapiro, DO, PC.)
Pig. 2 . Photograph of the left calf. (Courtesy of Marshall A. Shapiro, DO, PC.)
unfractionated heparin was initiated, therapeutic activated partial thromboplastin time values were monitored, and the patient was admitted to the medical service. Heparin therapy was continued, and the patient reported decreased symptoms; on hospital day 3, warfarin, 10 mg/d, was started. During hospital days 6 through 17, there was some difficulty maintaining the desired INR. Several times, with INRs between 3 and 5.18, vitamin I< was implemented, and warfarin administration was either reduced or held. O n hospital day 3, scant serosanguineous drainage and erythema were observed at the right hip incision. Although blood cultures were negative and the patient was afebrile, cefazolin, 1.O intravenous piggyback, was initiated empirically for cellulitis. O n hospital day 4, heparin and simvastatin were discontinued because of concerns that they may have precipitated a thrombocytopenia (platelet count, 131, O O O / p L ) . O n hospital day 7, a generalized reticular rash developed about the torso and lower extremities bilaterally. Cefazolin was discontinued, and the rash about the torso improved clinically. O n hospital day 9, the patient developed a fever ( 101.5"F) with a mild leukocytosis. The right hip became ecchymotic and swollen. Computed tomography of the right hip and abdomen was negative for hematoma, abscess, and lymphadenopathy. Warfarin was discontinued, and a working diagnosis of cutaneous necrosis related to warfarin therapy was proposed. The patient was heparinized, and her nutritional status was therapeutically supplemented. The following day, the left hip became ecchymotic, and bullae formed in the previously ecchymotic areas on the right hip (Figs. 1-3). A large area
of confluent ecchymosis with irregular borders was present throughout the buttocks, thighs, and lower extremities. A Greenfield filter and Quinton catheter were placed on August 26, 1998. An erythematous rash was noted about the patient's entire body. O n September 9, 1998 (hospital day 29) bilateral hip debridement was done by general surgery with a sharp carbon dioxide laser (left hip, 12 cm X 8 cm, and right hip, 12 cm X 13 cm, 16 cm X 16 cm, and 15 cm X 1 1 cm). The pathology report indicated necrotic tissue with multiple segments of eschar and necrotic fatty tissue, ischemic necrosis, and inflammation consistent with eschar. O n September 12, 1998, wide bilateral radical debridement of nonviable, full-thickness skin on the patient's
Pig. 3. Photograph of the left flank and thigh. (Courtesy of Marshall A. Shapiro, DO, PC.)
1072 The Journal of Arthroplasty Vol. 17 No. 8 December 2002 hips, thighs, buttocks, and calves was done. There was a 15% full-thickness skin loss. Transfer to a tertiary burn center occurred on September 13, 1998. The patient was made a M O code, suffered multiorgan failure, and died on September 22, 1998 (hospital day 42).
Discussion The oral anticoagulant warfarin is currently the most commonly used prophylaxis against venous thromboembolic disease in hip and knee arthroplasty patients [ 3-51. Currently the warfarin regimen is recognized as safe, cost-effective, and protective to the patient during the postoperative risk period [4,6]. The first case of warfarin-induced skin necrosis in the United States was reported in 1961, and there are >300 reports worldwide [S]. The cause of warfarin-induced skin necrosis remains elusive. Postulated are mechanisms that cause damage to veins and venules or alter the regulation of coagulation [ 31; these hypotheses include thrombosis, hypersensitivity, direct toxic effects of warfarin, vasculitis, and protein C deficiency [8,9]. Warfarin-induced skin necrosis is estimated to occur in 1 patient per 1,000 to 10,000 patients treated with warfarin, and previous exposure to warfarin therapy has not been shown to predispose patients to skin necrosis [ 51. It usually occurs 3 to 5 days after initiation of therapy and with large loading doses (ie, >10 mg) [7]. Review of the 3 largest studies of warfarin-induced skin necrosis showed that 82% of patients were female and mainly in their 50s and 60s (range, 16-93 years old). Of the cases, 74% to 90% occurred within 3 to 6 days of initiating treatment (range, 4 hours to 17 months). The cases had a n extremely high average loading dose of 24 mg [3]. A correlation between obesity and warfarin-induced skin necrosis has been noted; however, this correlation is not absolute [3,7,8]. Infection has been found in 25% of cases [7]. Most patients with warfarin-induced skin necrosis are undergoing prophylaxis or management of deep venous thrombosis or pulmonary embolus with concurrent hypercoagulable risk factors, such as stasis, tissue trauma, and fresh thrombi [7]. Warfarin-induced skin necrosis has a predilection for areas with high adipose tissue content, such as breast, buttocks, and thighs [S]. It may be that these areas are predisposed to thrombosis as a result of decreased blood flow and temperature and increased external pressure [7].
The first manifestations of warfarin-induced skin necrosis are pain, pressure, paresthesia, and erythema [S]. During the next 24 to 48 hours, hemorrhagic bullae develop, signifying irreversible fullthickness necrosis of the skin. Eventually the eschar that develops sloughs, revealing a lesion extending deep into the subcutaneous fat but usually sparing muscle [ 531. A biopsy specimen usually is obtained late in the progression of the disease; biopsy is not mandated for diagnosis, which is based instead on clinical grounds [ 5,8,11]. Prevention of warfarin-induced skin necrosis is the most efficacious method to limit morbidity and mortality and begins with the avoidance of large loading doses of warfarin [3]. If the patient had a prior episode of warfarin-induced skin necrosis, warfarin therapy may be started again but under extreme caution and while the patient is under cover of heparinization [3,8]. If the patient has a history of hepatobiliary disease; lupus; deficiencies of protein C, protein S, antithrombin 111, or vitamin I<; or a family history of thromboembolic events, the clinician must proceed carefully with oral anticoagulation [8] . Treatment of warfarin-induced skin necrosis is limited and primarily supportive [ 121, and the best outcomes may be expected if the early signs and symptoms are recognized. The most consistent early symptom is localized skin discomfort in areas with high adipose tissue content [3]. There are no signs that any form of treatment affects the progression of this disease after hemorrhagic bullae have formed [13,14]. At the first sign of skin necrosis, the generally accepted therapy should consist of discontinuation of warfarin and commencement of highdose heparin therapy until the lesions heal [8]. Lowmolecular weight heparin has been shown to be efficacious [lo]. Even with medical treatment, >50% of patients need surgery, which may include debridement, amputation, or skin grafting [5,8]. Mortality with all treatment modalities is 15Yoat 3 months [ 151.
Conclusion Given that warfarin is the most commonly used prophylaxis in orthopaedic antithromboembolic therapy and the 57th most often prescribed drug in the United States [16], the need to emphasize the potential severity of skin necrosis as a complication cannot be overstated. In addition to asking pertinent questions about personal and family history of coagulopathy and thromboembolic events, the clinician must remain vigilant for the early signs and symptoms of warfarin-induced skin necrosis.
Fatal Warfarin-Induced Skin Necrosis After THA
References 1. Cole MS, Minifee PI<, Wolma FJ: Coumarin necrosis: a review of the literature. Surgery 103:271, 1988 2. Bal BS, Gurba DM: Coumadin-induced necrosis of the skin after total knee replacement. J Bone Joint Surg Am 73:129, 1991 3. Eby CS: Warfarin-induced skin necrosis. Hematol Oncol Clin North Am 7:1291, 1993 4. Paiement GD, Green H: Thromboembolic disease in hip and knee replacement patients. p. 1. In Callaghan JJ, et a1 (eds): O.I<.U. Hip and Knee Reconstruction. American Academy of Orthopaedic Surgeons, Rosemont, IL, 1995 5. Sternberg ML, Pettyjohn FS: Warfarin sodium-induced skin necrosis. Ann Emerg Med 26:94, 1995 6. Hirsch J: Oral anticoagulant drugs. N Engl J Med 324:1865, 1991 7. Bauer I
10.
11. 12.
13.
14. 15.
16.
Clark and Bremner
1073
thrombosis, and shock. p. 113. In Cotran RS, I
Case Report
Fatal Warfarin-Induced Skin Necrosis After Total Hip Arthroplasty Jeffrey A. Clark, DO,* and Barron R. B. Bremner, D o t
Abstract: Skin necrosis associated with warfarin anticoagulation is a rare but serious complication. Few cases of warfarin-induced skin necrosis are found in the orthopaedic literature. We report a fatal case of warfarin-induced skin necrosis after total hip arthroplasty. Key words: total hip arthroplasty (THA), warfarin, fatal skin necrosis. Copyright 2002, Elsevier Science (USA). All rights reserved.
Skin necrosis associated with warfarin is rare. The complication is of sudden onset and can cause significant morbidity and is potentially lethal [ 11. We report a case of extensive skin necrosis over the buttocks and lower extremities after total hip arthroplasty (THA) that resulted in the death of the patient. To our knowledge, warfarin-induced skin necrosis has been reported only once in the orthopaedic literature [2]. Recognizing the complications of warfarin anticoagulation therapy requires a n appropriate index of suspicion in the proper clinical setting.
Case Report A 70-year-old white woman had a right THA for degenerative joint disease done on June 22, 1998. From the *Department of Orthopaedics, Michigan State University, Garden City Hospital, Garden City, Michigan; and fosteopathic Medical Center, Des Moines University, Des Moines, Iowa. Submitted September 28, 2001; accepted April 10, 2002. No benefits or funds were received in support of this study. Reprint requests: Barron R. B. Bremner, DO, 819 48th Aven u e N W , Rochester, MN 55901. E-mail: bremner.barron@ mayo .edu Copyright 2002, Elsevier Science (USA).All rights reserved. 0883-5403/02/1708-0029$35.00/0 doi:10.1054/a1th.2002.34816
Significant medical history included hypertension, hypercholesterolemia, obesity, and right breast cancer with lumpectomy and radiation. There was no history of stroke, deep venous thrombosis, or other thromboembolic events. Medications on admission included fosinopril, simvastatin, iron sulfate, hydrocodone, and tamoxifen. There was no previous history of warfarin therapy. Results of coagulation studies, thyroid function tests, urinalysis, and other laboratory data were unremarkable. One day before the THA, the patient was given a 5.0-mg dose of warfarin. No complications were reported during the operation. Postoperatively, warfarin dosing was adjusted to achieve a desired international normalized ratio (INR) between 2.0 and 3.0 for a total of 21 days after surgery. The patient was discharged on postoperative day 5 with no reported complications. Office follow-up visits were routine, and the patient was reporting minimal pain and ambulating independently. O n August 11, 1998, during a scheduled office follow-up, the patient complained of right leg swelling and pain. Referral to the emergency department was made, and a n ultrasound study revealed extensive thrombi in the proximal vessels of the right lower extremity. Intravenous
1070
Fatal Warfarin-Induced Skin Necrosis After THA
Clark and Bremner
1071
Pig. 1. Photograph of the right lateral thigh. (Courtesy of Marshall A. Shapiro, DO, PC.)
Pig. 2 . Photograph of the left calf. (Courtesy of Marshall A. Shapiro, DO, PC.)
unfractionated heparin was initiated, therapeutic activated partial thromboplastin time values were monitored, and the patient was admitted to the medical service. Heparin therapy was continued, and the patient reported decreased symptoms; on hospital day 3, warfarin, 10 mg/d, was started. During hospital days 6 through 17, there was some difficulty maintaining the desired INR. Several times, with INRs between 3 and 5.18, vitamin I< was implemented, and warfarin administration was either reduced or held. O n hospital day 3, scant serosanguineous drainage and erythema were observed at the right hip incision. Although blood cultures were negative and the patient was afebrile, cefazolin, 1.O intravenous piggyback, was initiated empirically for cellulitis. O n hospital day 4, heparin and simvastatin were discontinued because of concerns that they may have precipitated a thrombocytopenia (platelet count, 131, O O O / p L ) . O n hospital day 7, a generalized reticular rash developed about the torso and lower extremities bilaterally. Cefazolin was discontinued, and the rash about the torso improved clinically. O n hospital day 9, the patient developed a fever ( 101.5"F) with a mild leukocytosis. The right hip became ecchymotic and swollen. Computed tomography of the right hip and abdomen was negative for hematoma, abscess, and lymphadenopathy. Warfarin was discontinued, and a working diagnosis of cutaneous necrosis related to warfarin therapy was proposed. The patient was heparinized, and her nutritional status was therapeutically supplemented. The following day, the left hip became ecchymotic, and bullae formed in the previously ecchymotic areas on the right hip (Figs. 1-3). A large area
of confluent ecchymosis with irregular borders was present throughout the buttocks, thighs, and lower extremities. A Greenfield filter and Quinton catheter were placed on August 26, 1998. An erythematous rash was noted about the patient's entire body. O n September 9, 1998 (hospital day 29) bilateral hip debridement was done by general surgery with a sharp carbon dioxide laser (left hip, 12 cm X 8 cm, and right hip, 12 cm X 13 cm, 16 cm X 16 cm, and 15 cm X 1 1 cm). The pathology report indicated necrotic tissue with multiple segments of eschar and necrotic fatty tissue, ischemic necrosis, and inflammation consistent with eschar. O n September 12, 1998, wide bilateral radical debridement of nonviable, full-thickness skin on the patient's
Pig. 3. Photograph of the left flank and thigh. (Courtesy of Marshall A. Shapiro, DO, PC.)
1072 The Journal of Arthroplasty Vol. 17 No. 8 December 2002 hips, thighs, buttocks, and calves was done. There was a 15% full-thickness skin loss. Transfer to a tertiary burn center occurred on September 13, 1998. The patient was made a M O code, suffered multiorgan failure, and died on September 22, 1998 (hospital day 42).
Discussion The oral anticoagulant warfarin is currently the most commonly used prophylaxis against venous thromboembolic disease in hip and knee arthroplasty patients [ 3-51. Currently the warfarin regimen is recognized as safe, cost-effective, and protective to the patient during the postoperative risk period [4,6]. The first case of warfarin-induced skin necrosis in the United States was reported in 1961, and there are >300 reports worldwide [S]. The cause of warfarin-induced skin necrosis remains elusive. Postulated are mechanisms that cause damage to veins and venules or alter the regulation of coagulation [ 31; these hypotheses include thrombosis, hypersensitivity, direct toxic effects of warfarin, vasculitis, and protein C deficiency [8,9]. Warfarin-induced skin necrosis is estimated to occur in 1 patient per 1,000 to 10,000 patients treated with warfarin, and previous exposure to warfarin therapy has not been shown to predispose patients to skin necrosis [ 51. It usually occurs 3 to 5 days after initiation of therapy and with large loading doses (ie, >10 mg) [7]. Review of the 3 largest studies of warfarin-induced skin necrosis showed that 82% of patients were female and mainly in their 50s and 60s (range, 16-93 years old). Of the cases, 74% to 90% occurred within 3 to 6 days of initiating treatment (range, 4 hours to 17 months). The cases had a n extremely high average loading dose of 24 mg [3]. A correlation between obesity and warfarin-induced skin necrosis has been noted; however, this correlation is not absolute [3,7,8]. Infection has been found in 25% of cases [7]. Most patients with warfarin-induced skin necrosis are undergoing prophylaxis or management of deep venous thrombosis or pulmonary embolus with concurrent hypercoagulable risk factors, such as stasis, tissue trauma, and fresh thrombi [7]. Warfarin-induced skin necrosis has a predilection for areas with high adipose tissue content, such as breast, buttocks, and thighs [S]. It may be that these areas are predisposed to thrombosis as a result of decreased blood flow and temperature and increased external pressure [7].
The first manifestations of warfarin-induced skin necrosis are pain, pressure, paresthesia, and erythema [S]. During the next 24 to 48 hours, hemorrhagic bullae develop, signifying irreversible fullthickness necrosis of the skin. Eventually the eschar that develops sloughs, revealing a lesion extending deep into the subcutaneous fat but usually sparing muscle [ 531. A biopsy specimen usually is obtained late in the progression of the disease; biopsy is not mandated for diagnosis, which is based instead on clinical grounds [ 5,8,11]. Prevention of warfarin-induced skin necrosis is the most efficacious method to limit morbidity and mortality and begins with the avoidance of large loading doses of warfarin [3]. If the patient had a prior episode of warfarin-induced skin necrosis, warfarin therapy may be started again but under extreme caution and while the patient is under cover of heparinization [3,8]. If the patient has a history of hepatobiliary disease; lupus; deficiencies of protein C, protein S, antithrombin 111, or vitamin I<; or a family history of thromboembolic events, the clinician must proceed carefully with oral anticoagulation [8] . Treatment of warfarin-induced skin necrosis is limited and primarily supportive [ 121, and the best outcomes may be expected if the early signs and symptoms are recognized. The most consistent early symptom is localized skin discomfort in areas with high adipose tissue content [3]. There are no signs that any form of treatment affects the progression of this disease after hemorrhagic bullae have formed [13,14]. At the first sign of skin necrosis, the generally accepted therapy should consist of discontinuation of warfarin and commencement of highdose heparin therapy until the lesions heal [8]. Lowmolecular weight heparin has been shown to be efficacious [lo]. Even with medical treatment, >50% of patients need surgery, which may include debridement, amputation, or skin grafting [5,8]. Mortality with all treatment modalities is 15Yoat 3 months [ 151.
Conclusion Given that warfarin is the most commonly used prophylaxis in orthopaedic antithromboembolic therapy and the 57th most often prescribed drug in the United States [16], the need to emphasize the potential severity of skin necrosis as a complication cannot be overstated. In addition to asking pertinent questions about personal and family history of coagulopathy and thromboembolic events, the clinician must remain vigilant for the early signs and symptoms of warfarin-induced skin necrosis.
Fatal Warfarin-Induced Skin Necrosis After THA
References 1. Cole MS, Minifee PI<, Wolma FJ: Coumarin necrosis: a review of the literature. Surgery 103:271, 1988 2. Bal BS, Gurba DM: Coumadin-induced necrosis of the skin after total knee replacement. J Bone Joint Surg Am 73:129, 1991 3. Eby CS: Warfarin-induced skin necrosis. Hematol Oncol Clin North Am 7:1291, 1993 4. Paiement GD, Green H: Thromboembolic disease in hip and knee replacement patients. p. 1. In Callaghan JJ, et a1 (eds): O.I<.U. Hip and Knee Reconstruction. American Academy of Orthopaedic Surgeons, Rosemont, IL, 1995 5. Sternberg ML, Pettyjohn FS: Warfarin sodium-induced skin necrosis. Ann Emerg Med 26:94, 1995 6. Hirsch J: Oral anticoagulant drugs. N Engl J Med 324:1865, 1991 7. Bauer I
10.
11. 12.
13.
14. 15.
16.
Clark and Bremner
1073
thrombosis, and shock. p. 113. In Cotran RS, I