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Surgery-Associated Factor VIII Inhibitors in Patients without Hemophilia
Surgery-Associated Factor VIII Inhibitors In Patients without Hemophilia JOSHI ALUMKAL, MD; LAWRENCE RICE, MD; HYMA VEMPATHY, MD; JOHN J. McCARTHY, MD; SHIRLEY A. RIGGS, MD
ABSTRACT: The acquisition of antibodies to factor VIII (ie, factor VIII protein) by patients without hemophilia is associated with conditions such as pregnancy, lymphoma, and autoimmune disorders. We present three patients who acquired factor VIII antibodies in the postoperative setting. Preoperatively, none gave a history of bleeding even with past surgeries and all had normal coagulation tests. Within days of surgery (bowel resection, cholecystectomy, coronary bypass), a bleeding diathesis emerged with prolonged partial thromboplastin time, decreased factor VIII levels, and demonstrable factor VIII antibodies. All patients required multiple blood transfusions and urgent re-
F
actor VIII (ie, factor VIII protein) antibodies (coagulation inhibitors, circulating anticoagulants, acquired hemophilia) emerging in patients without hemophilia often produce severe or lifethreatening hemorrhage, and management can challenge the most skilled clinician. Prevalence is only 0.2 to 2.5 per million people. Half the time, there is an associated underlying disorder such as autoimmune disease (lupus, ulcerative colitis) in 18%, peripartum state in 10%, and lymphoid or solid tumors in another 10%.1,2 Surgery has not been recognized as a cause of factor VIII inhibitors, but our experience with three patients suggests an association. Our experience highlights acquired hemophilia as a consideration in patients experiencing unusual postoperative bleeding. Case Reports See case summaries in Table 1.
Case 1 A 47-year-old man with a history of congestive cardiomyopathy, atrial septal defect repair, and chronic atrial fibrillation presented
From the Section of Hematology, Department of Medicine, Baylor College of Medicine and The Methodist Hospital, Houston, Texas. Submitted August 14, 1998; accepted in revised form January 4, 1999. Correspondence: Lawrence Rice, M.D., 6565 Fannin, MS 902Main, Houston, TX 77030 (E-mail: lrice®tmh.tmc.edu).
350
exploration for hemostatic control. All were treated with high dose human factor VIII infusions, corticosteroids, and various forms of immunosuppression. We wish to raise awareness of surgery as a precipitating cause of acquired hemophilia, which is something to be considered with unusual postoperative bleeding. This syndrome is remarkable for its abrupt onset within days of surgery, dramatic bleeding, subsequent persistence, but potential reversal by immunosuppression. KEY INDEXING TERMS: Hemophilia; Acquired hemophilia; Factor 8 inhibitors; Circulating anticoagulants; Surgical bleeding [Am J Med Sci
1999;318(5):350-2.]
with an acute abdomen in October 1988. At surgery, necrotic small and large bowel were resected. No source of emboli was identified. The activated partial thromboplastin time (aPTT) was 30 seconds immediately after the operation (normal, 27-37 seconds). Ampicillin and, later, ticarcillin-clavulanic acid and clindamycin were administered. On postoperative day (POD) 4, there was a dramatic fall in hematocrit and prolongation of aPTT. CT scan of the abdomen revealed a 4-liter collection of blood. Coagulation studies, including fibrinogen, fibrin-split products, and factor levels were normal, except for a factor VIII level that was initially 14%. An inhibitor was identified with an initial titer3 of 3.25 Bethesda units (a Bethesda unit is the amount of inhibitor that will inactivate 50% or 0.5 unit of a coagulation factor during the incubation period). The patient required multiple units of packed red cells. When cryoprecipitate therapy failed, treatment was instituted with large doses of heattreated and monoclonal antibody-purified factor VIII (lO,OOO-unit bolus and 1,000 unitslh), DDAVP, corticosteroids (initially 500 mg of methyl-prednisolone) and high-dose intravenous immunoglobulin. Two surgical re-explorations drained hematomas. Because of difficulty maintaining factor VIII levels and continued clinical bleeding, two plasma exchanges were performed and higher doses of factor VIII were given. After 40 days of therapy, factor VIII was stable at 100% without replacement therapy. Corticosteroids were gradually reduced without recurrence of the inhibitor.
Case 2 In 1985, a 70-year-old woman had a cholecystectomy after having recovered from recent cholecystitis. Prior abdominal hysterectomy and cataract surgeries were uncomplicated. Preoperative coagulation studies, including aPTT, were normal. On POD 1, the operative site and drain oozed more blood than usual. On POD 4, there was a hematoma in the operative bed and purpura on the abdominal wall. The aPTT, at 50 seconds, was prolonged (normal, 25-37 seconds). A 1: 1 mix of the patient's plasma with normal plasma corrected this at first, but the aPIT was again prolonged after incubation. Factor VIII was 6%. Three days later it was 1%, and an inhibitor titer was 5 Bethesda units. Multiple units of red blood cells were transfused. November 1999 Volume 318 Number 5
Alumkol et 01
Table 1. Case Summaries Bleeding Symptoms
Inhibitor Level (BU)
Immunosuppressive Treatment
Case
Age/Sex
Surgery
1
471M
POD 4
Intra-abdominal
3.25
Steroids, IVIG, plasma exchange
Continued remission
2
701F
Resection of ischemic bowel Cholecystectomy
POD 4 (? earlier)
Intra-abdominal; later skin
5, later 46
Steroids, 6 MP
3
741F
Coronary artery bypass grafting
POD 7 (? earlier)
Chest tubes, tracheostomy, GI tract; later tongue and skin
16, later 200
Steroids, cyclophosphamide
Died of liver complications in remission Continued low titer inhibitor
Day of Onset
Follow-up
BU, Bethesda units; IVIG, intravenous immunoglobulin; 6MP, 6-mercaptopurine
Surgical wound exploration, debridement, and drainage were accomplished with infusion of high-dose, heat-treated factor VIII concentrate (an infusion of 1000 units per hour proved effective), maintaining 50 to 70% factor activity for 1 week. The patient was discharged asymptomatic on no therapy with aPTT 66 seconds and factor VIII less than 1%. Five months later, diffuse spontaneous purpura and subcutaneous hematomas were increasing. aPTT was 95 seconds and Bethesda titer was 46 units. Transfusion-related hepatitis (non-A, non-B) was apparent as well. Prednisone (60 mg daily) and 6-mercaptopurine (100 mg daily) were begun. After 2 months, the factor VIII inhibitor was undetectable and immunosuppressive therapy was stopped. After another month, new purpura and hematomas appeared with relapse of the inhibitor. Mercaptopurine was reinstituted with prompt remission. Unfortunately, the patient suffered an unusually aggressive hepatitis course that did not improve when 6-mercaptopurine was stopped. She died of complications from liver failure 13 months after the cholecystectomy, with no detectable factor VIII antibodies.
Case 3 A 74-year-old woman with peripheral vascular disease and prior cerebrovascular accident had coronary artery bypass in 1987. There was no bleeding with prior hysterectomy. Blood loss with the bypass surgery (estimated 1200 mL) was more than usual, requiring re-exploration on POD 1. On POD 2, there was sepsis and adult respiratory distress syndrome requiring pressors, mechanical ventilation, and use of ceftazidime and vancomycin. The aPTT on that day was 35 seconds. Tracheostomy was performed on POD 7. On POD 8, there was oozing from the tracheostomy site and gastrointestinal bleeding; aPTT was prolonged. Plasma mixing studies revealed an inhibitor and factor VIII was 1%. (Later inhibitor titer was 16 Bethesda units.) The patient required multiple transfusions of packed red cells. High doses of human factor VIII were successful in correcting her hemostatic problems and allowed recovery from her postoperative complications. Two months later, a large spontaneous hematoma of her tongue mandated readmission. Inhibitor titer had increased to 200 units. Therapy was initiated with activated factor concentrate (Autoplex 100 units/kg) and cyclophosphamide (initially 150 mg daily). The cyclophosphamide was stopped after few months. Over the last 8 years, the patient has remained minimally symptomatic from a bruising tendency with no therapy. Her most recent inhibitor titer was 6.5 Bethesda units.
Discussion
The lack of histories of bleeding, normal coagulation tests before and/or immediately after the surgeries, and abrupt onset in the immediate postoperTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
ative period build a strong case that surgery causally triggered acquired hemophilia in these three patients. Indeed, other isolated case reports implicate surgery in factor VIII antibody development,4,5 although only one publication in French fully delineates the syndrome in a cholecystectomy patient with normal preoperative coagulation tests. 4 In addition to the three patients reported here, we have seen others in whom surgery has played some role in coagulation inhibitor development. For example, one young man required emergency colectomy for toxic megacolon complicating ulcerative colitis, and his immediate postoperative course was complicated by a therapy-refractory high-titer factor VIII inhibitor eventually leading to death. 6 This patient is not included as a fourth case in our series because ulcerative colitis is known to be associated with factor VIII antibodies and because, in retrospect, prolongation of the aPTT was first noted immediately before surgery. Another patient developed a transient factor V inhibitor after back surgery, and other authors have associated surgery with factor V antibodies. 7 ,8 Surgical procedures employing topical bovine thrombin are known to be associated with antibody formation. Antibodies range from clinically insignificant antibovine thrombin to important antibodies cross-reacting with human coagulation proteins. 9 None of our patients was exposed to thrombin glue. How surgery induces factor VIII antibodies is open to speculation. It could be related to trauma and tissue injury, to immune dysregulation accompanying surgery,lO or possibly to a reaction to anesthetic agents or other drugs. None of the drugs our patients received has been associated with coagulation factor inhibitors. A role of exposure to blood products seems unlikely given the time course and the lack of preinhibitor transfusion in at least one of our patients. It should be noted that our patients lacked any evidence of predisposing conditions for coagulation inhibitors such as paraproteinemias, lymphoproliferative diseases, or autoimmune diseases. 351
Acquired Hemophilia with Surgery
In confronting a patient with excessive postoperative bleeding, we recommend that the possibility of factor VIII antibodies be considered, even very soon after surgery and with bleeding confined to the surgical site. The aPTT test is an adequate screen, because the results are abnormal except with the weakest of inhibitors. A simple 1:1 mix of patient plasma and normal plasma to distinguish factor deficiency from inhibitor is not sufficient; it is crucial to incubate the mix for 1 to 2 h. As seen in two of our patients, there is often immediate correction with the 1:1 mix; prolongation is seen only during incubation because of the binding kinetics of factor VIII antibodies. l l As illustrated by our cases, factor VIII inhibitors commonly produce severe or life-threatening hemorrhage; understandably, this presents a special challenge in a patient who has just undergone major surgery. Therapeutic options to establish hemostasis include high-dose infusions of factor VIII, porcine factor VIII, activated coagulation factor concentrates with factor VIII bypassing activity, and there has been recent interest in purified factor Vila. 12 The antibodies are uncommonly transient with spontaneous resolution; immunosuppressive therapies are usually required for long-term management. Immunosuppressive therapies include corticosteroids, intravenous y-globulin, plasma exchange, and other immunosuppressive and/or cytotoxic drugs. Our experience with several other acquired hemophilia patients supports a high success rate with cyclophosphamide, as reported by others.13 In summary, our series supports an association of surgery with the triggering of factor VIII antibodies. Remarkably, this syndrome presents with abrupt bleeding in the first few days after surgery. Awareness can facilitate appropriate life-saving intervention. Once triggered, the acquired hemophilia becomes chronic but may be reversed by immunosuppressive therapies.
352
Acknowledgments
We thank Dr. Steven Kalter for providing updates on one patient. References 1. Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981; 45:200-3. 2. Kessler CM. The treatment of acquired factor VIII inhibitors: worldwide experience with porcine factor VIII. In: Kessler C, editor. Acquired hemophilia. Princeton (NJ): Excerpta Medica Inc; 1995. p. pp. 71-89. 3. Kasper CK, Aledort L, Aronson D, et aI. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975;34:869-72. 4. Huraux C, Hidou M, Perrier JF, et al. Apparition d'un anticoagulant circulant antifacteur VIII apres chirurgie de la voie biliaire (Development of an antifactor VIII circulating anticoagulant after biliary surgery.) Ann Fr Anesth Reanim 1994;13:138-41. 5. Priluck IA, Howe RB, Eifrig DE, et al. Retinal surgery complicated by a spontaneously acquired Factor VIII inhibitor. Am J Ophthalmol 1978;86:27-30. 6. Waddell CC, Ashton CM, Brown JA. Use of porcine factor VIII concentrate [letter]. JAMA 1985;253:344. 7. Feinstein DI. Acquired inhibitor of factor V. Thromb Haemost 1978;39:663-74. 8. Nesheim ME, Nichols WL, Cole TL. Isolation and study of an acquired inhibitor of human coagulation factor V. J Clin Invest 1986;77:405-15. 9. Zehnder JL, Leung LLK. Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin. Blood 1990;76:2011-6. 10. Redmond HP, Watson RWG, Houghton T, et aI. Immune function in patients undergoing open vs. laparoscopic cholecystectomy Arch Surg 1994;129:1240-6. 11. Lossing T, Kasper CK, Feinstein DI. Detection of factor VIII inhibitors with the activated partial thromboplastin time. Blood 1977;49:793-7. 12. White GC, Roberts HR. The treatment of Factor VIII inhibitors-A general overview. Vox Sang 1996;70(Suppl 1): 19-23. 13. Schaffer LG, Phillips MD. Successful treatment of acquired hemophilia with oral immunosuppressive therapy. Ann Intern Med 1997;127:206-9.
November 1999 Volume 318 Number 5
ABSTRACT: The acquisition of antibodies to factor VIII (ie, factor VIII protein) by patients without hemophilia is associated with conditions such as pregnancy, lymphoma, and autoimmune disorders. We present three patients who acquired factor VIII antibodies in the postoperative setting. Preoperatively, none gave a history of bleeding even with past surgeries and all had normal coagulation tests. Within days of surgery (bowel resection, cholecystectomy, coronary bypass), a bleeding diathesis emerged with prolonged partial thromboplastin time, decreased factor VIII levels, and demonstrable factor VIII antibodies. All patients required multiple blood transfusions and urgent re-
F
actor VIII (ie, factor VIII protein) antibodies (coagulation inhibitors, circulating anticoagulants, acquired hemophilia) emerging in patients without hemophilia often produce severe or lifethreatening hemorrhage, and management can challenge the most skilled clinician. Prevalence is only 0.2 to 2.5 per million people. Half the time, there is an associated underlying disorder such as autoimmune disease (lupus, ulcerative colitis) in 18%, peripartum state in 10%, and lymphoid or solid tumors in another 10%.1,2 Surgery has not been recognized as a cause of factor VIII inhibitors, but our experience with three patients suggests an association. Our experience highlights acquired hemophilia as a consideration in patients experiencing unusual postoperative bleeding. Case Reports See case summaries in Table 1.
Case 1 A 47-year-old man with a history of congestive cardiomyopathy, atrial septal defect repair, and chronic atrial fibrillation presented
From the Section of Hematology, Department of Medicine, Baylor College of Medicine and The Methodist Hospital, Houston, Texas. Submitted August 14, 1998; accepted in revised form January 4, 1999. Correspondence: Lawrence Rice, M.D., 6565 Fannin, MS 902Main, Houston, TX 77030 (E-mail: lrice®tmh.tmc.edu).
350
exploration for hemostatic control. All were treated with high dose human factor VIII infusions, corticosteroids, and various forms of immunosuppression. We wish to raise awareness of surgery as a precipitating cause of acquired hemophilia, which is something to be considered with unusual postoperative bleeding. This syndrome is remarkable for its abrupt onset within days of surgery, dramatic bleeding, subsequent persistence, but potential reversal by immunosuppression. KEY INDEXING TERMS: Hemophilia; Acquired hemophilia; Factor 8 inhibitors; Circulating anticoagulants; Surgical bleeding [Am J Med Sci
1999;318(5):350-2.]
with an acute abdomen in October 1988. At surgery, necrotic small and large bowel were resected. No source of emboli was identified. The activated partial thromboplastin time (aPTT) was 30 seconds immediately after the operation (normal, 27-37 seconds). Ampicillin and, later, ticarcillin-clavulanic acid and clindamycin were administered. On postoperative day (POD) 4, there was a dramatic fall in hematocrit and prolongation of aPTT. CT scan of the abdomen revealed a 4-liter collection of blood. Coagulation studies, including fibrinogen, fibrin-split products, and factor levels were normal, except for a factor VIII level that was initially 14%. An inhibitor was identified with an initial titer3 of 3.25 Bethesda units (a Bethesda unit is the amount of inhibitor that will inactivate 50% or 0.5 unit of a coagulation factor during the incubation period). The patient required multiple units of packed red cells. When cryoprecipitate therapy failed, treatment was instituted with large doses of heattreated and monoclonal antibody-purified factor VIII (lO,OOO-unit bolus and 1,000 unitslh), DDAVP, corticosteroids (initially 500 mg of methyl-prednisolone) and high-dose intravenous immunoglobulin. Two surgical re-explorations drained hematomas. Because of difficulty maintaining factor VIII levels and continued clinical bleeding, two plasma exchanges were performed and higher doses of factor VIII were given. After 40 days of therapy, factor VIII was stable at 100% without replacement therapy. Corticosteroids were gradually reduced without recurrence of the inhibitor.
Case 2 In 1985, a 70-year-old woman had a cholecystectomy after having recovered from recent cholecystitis. Prior abdominal hysterectomy and cataract surgeries were uncomplicated. Preoperative coagulation studies, including aPTT, were normal. On POD 1, the operative site and drain oozed more blood than usual. On POD 4, there was a hematoma in the operative bed and purpura on the abdominal wall. The aPTT, at 50 seconds, was prolonged (normal, 25-37 seconds). A 1: 1 mix of the patient's plasma with normal plasma corrected this at first, but the aPIT was again prolonged after incubation. Factor VIII was 6%. Three days later it was 1%, and an inhibitor titer was 5 Bethesda units. Multiple units of red blood cells were transfused. November 1999 Volume 318 Number 5
Alumkol et 01
Table 1. Case Summaries Bleeding Symptoms
Inhibitor Level (BU)
Immunosuppressive Treatment
Case
Age/Sex
Surgery
1
471M
POD 4
Intra-abdominal
3.25
Steroids, IVIG, plasma exchange
Continued remission
2
701F
Resection of ischemic bowel Cholecystectomy
POD 4 (? earlier)
Intra-abdominal; later skin
5, later 46
Steroids, 6 MP
3
741F
Coronary artery bypass grafting
POD 7 (? earlier)
Chest tubes, tracheostomy, GI tract; later tongue and skin
16, later 200
Steroids, cyclophosphamide
Died of liver complications in remission Continued low titer inhibitor
Day of Onset
Follow-up
BU, Bethesda units; IVIG, intravenous immunoglobulin; 6MP, 6-mercaptopurine
Surgical wound exploration, debridement, and drainage were accomplished with infusion of high-dose, heat-treated factor VIII concentrate (an infusion of 1000 units per hour proved effective), maintaining 50 to 70% factor activity for 1 week. The patient was discharged asymptomatic on no therapy with aPTT 66 seconds and factor VIII less than 1%. Five months later, diffuse spontaneous purpura and subcutaneous hematomas were increasing. aPTT was 95 seconds and Bethesda titer was 46 units. Transfusion-related hepatitis (non-A, non-B) was apparent as well. Prednisone (60 mg daily) and 6-mercaptopurine (100 mg daily) were begun. After 2 months, the factor VIII inhibitor was undetectable and immunosuppressive therapy was stopped. After another month, new purpura and hematomas appeared with relapse of the inhibitor. Mercaptopurine was reinstituted with prompt remission. Unfortunately, the patient suffered an unusually aggressive hepatitis course that did not improve when 6-mercaptopurine was stopped. She died of complications from liver failure 13 months after the cholecystectomy, with no detectable factor VIII antibodies.
Case 3 A 74-year-old woman with peripheral vascular disease and prior cerebrovascular accident had coronary artery bypass in 1987. There was no bleeding with prior hysterectomy. Blood loss with the bypass surgery (estimated 1200 mL) was more than usual, requiring re-exploration on POD 1. On POD 2, there was sepsis and adult respiratory distress syndrome requiring pressors, mechanical ventilation, and use of ceftazidime and vancomycin. The aPTT on that day was 35 seconds. Tracheostomy was performed on POD 7. On POD 8, there was oozing from the tracheostomy site and gastrointestinal bleeding; aPTT was prolonged. Plasma mixing studies revealed an inhibitor and factor VIII was 1%. (Later inhibitor titer was 16 Bethesda units.) The patient required multiple transfusions of packed red cells. High doses of human factor VIII were successful in correcting her hemostatic problems and allowed recovery from her postoperative complications. Two months later, a large spontaneous hematoma of her tongue mandated readmission. Inhibitor titer had increased to 200 units. Therapy was initiated with activated factor concentrate (Autoplex 100 units/kg) and cyclophosphamide (initially 150 mg daily). The cyclophosphamide was stopped after few months. Over the last 8 years, the patient has remained minimally symptomatic from a bruising tendency with no therapy. Her most recent inhibitor titer was 6.5 Bethesda units.
Discussion
The lack of histories of bleeding, normal coagulation tests before and/or immediately after the surgeries, and abrupt onset in the immediate postoperTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
ative period build a strong case that surgery causally triggered acquired hemophilia in these three patients. Indeed, other isolated case reports implicate surgery in factor VIII antibody development,4,5 although only one publication in French fully delineates the syndrome in a cholecystectomy patient with normal preoperative coagulation tests. 4 In addition to the three patients reported here, we have seen others in whom surgery has played some role in coagulation inhibitor development. For example, one young man required emergency colectomy for toxic megacolon complicating ulcerative colitis, and his immediate postoperative course was complicated by a therapy-refractory high-titer factor VIII inhibitor eventually leading to death. 6 This patient is not included as a fourth case in our series because ulcerative colitis is known to be associated with factor VIII antibodies and because, in retrospect, prolongation of the aPTT was first noted immediately before surgery. Another patient developed a transient factor V inhibitor after back surgery, and other authors have associated surgery with factor V antibodies. 7 ,8 Surgical procedures employing topical bovine thrombin are known to be associated with antibody formation. Antibodies range from clinically insignificant antibovine thrombin to important antibodies cross-reacting with human coagulation proteins. 9 None of our patients was exposed to thrombin glue. How surgery induces factor VIII antibodies is open to speculation. It could be related to trauma and tissue injury, to immune dysregulation accompanying surgery,lO or possibly to a reaction to anesthetic agents or other drugs. None of the drugs our patients received has been associated with coagulation factor inhibitors. A role of exposure to blood products seems unlikely given the time course and the lack of preinhibitor transfusion in at least one of our patients. It should be noted that our patients lacked any evidence of predisposing conditions for coagulation inhibitors such as paraproteinemias, lymphoproliferative diseases, or autoimmune diseases. 351
Acquired Hemophilia with Surgery
In confronting a patient with excessive postoperative bleeding, we recommend that the possibility of factor VIII antibodies be considered, even very soon after surgery and with bleeding confined to the surgical site. The aPTT test is an adequate screen, because the results are abnormal except with the weakest of inhibitors. A simple 1:1 mix of patient plasma and normal plasma to distinguish factor deficiency from inhibitor is not sufficient; it is crucial to incubate the mix for 1 to 2 h. As seen in two of our patients, there is often immediate correction with the 1:1 mix; prolongation is seen only during incubation because of the binding kinetics of factor VIII antibodies. l l As illustrated by our cases, factor VIII inhibitors commonly produce severe or life-threatening hemorrhage; understandably, this presents a special challenge in a patient who has just undergone major surgery. Therapeutic options to establish hemostasis include high-dose infusions of factor VIII, porcine factor VIII, activated coagulation factor concentrates with factor VIII bypassing activity, and there has been recent interest in purified factor Vila. 12 The antibodies are uncommonly transient with spontaneous resolution; immunosuppressive therapies are usually required for long-term management. Immunosuppressive therapies include corticosteroids, intravenous y-globulin, plasma exchange, and other immunosuppressive and/or cytotoxic drugs. Our experience with several other acquired hemophilia patients supports a high success rate with cyclophosphamide, as reported by others.13 In summary, our series supports an association of surgery with the triggering of factor VIII antibodies. Remarkably, this syndrome presents with abrupt bleeding in the first few days after surgery. Awareness can facilitate appropriate life-saving intervention. Once triggered, the acquired hemophilia becomes chronic but may be reversed by immunosuppressive therapies.
352
Acknowledgments
We thank Dr. Steven Kalter for providing updates on one patient. References 1. Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981; 45:200-3. 2. Kessler CM. The treatment of acquired factor VIII inhibitors: worldwide experience with porcine factor VIII. In: Kessler C, editor. Acquired hemophilia. Princeton (NJ): Excerpta Medica Inc; 1995. p. pp. 71-89. 3. Kasper CK, Aledort L, Aronson D, et aI. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975;34:869-72. 4. Huraux C, Hidou M, Perrier JF, et al. Apparition d'un anticoagulant circulant antifacteur VIII apres chirurgie de la voie biliaire (Development of an antifactor VIII circulating anticoagulant after biliary surgery.) Ann Fr Anesth Reanim 1994;13:138-41. 5. Priluck IA, Howe RB, Eifrig DE, et al. Retinal surgery complicated by a spontaneously acquired Factor VIII inhibitor. Am J Ophthalmol 1978;86:27-30. 6. Waddell CC, Ashton CM, Brown JA. Use of porcine factor VIII concentrate [letter]. JAMA 1985;253:344. 7. Feinstein DI. Acquired inhibitor of factor V. Thromb Haemost 1978;39:663-74. 8. Nesheim ME, Nichols WL, Cole TL. Isolation and study of an acquired inhibitor of human coagulation factor V. J Clin Invest 1986;77:405-15. 9. Zehnder JL, Leung LLK. Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin. Blood 1990;76:2011-6. 10. Redmond HP, Watson RWG, Houghton T, et aI. Immune function in patients undergoing open vs. laparoscopic cholecystectomy Arch Surg 1994;129:1240-6. 11. Lossing T, Kasper CK, Feinstein DI. Detection of factor VIII inhibitors with the activated partial thromboplastin time. Blood 1977;49:793-7. 12. White GC, Roberts HR. The treatment of Factor VIII inhibitors-A general overview. Vox Sang 1996;70(Suppl 1): 19-23. 13. Schaffer LG, Phillips MD. Successful treatment of acquired hemophilia with oral immunosuppressive therapy. Ann Intern Med 1997;127:206-9.
November 1999 Volume 318 Number 5