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Acquired Hemophilia a Presenting as a Bleeding Diathesis in a Postpartum Patient: Diagnosis and Management
ACQUIRED HEMOPHILIA A PRESENTING AS A BLEEDING DIATHESIS IN A POSTPARTUM PATIENT: DIAGNOSIS AND MANAGEMENT Mary-Frances Scully, MD, MRCPI, FRCPC, I Wael Shublaq, MBBCH, DP OB/GYN, PhD, I Gillian D. Oliver, MD, FRCSC(c), FACOGz iMemorial UniverSity of Newfoundland, Health Science Centre, St.John's NF 2Grand River Hospital, Kitchener ON
Abstract: Antibodies against Factor VIII (FVIII) can develop in non-hemophiliac patients, causing the rare condition of acquired hemophilia. In 7.3% of the patients, the FVIII inhibitors appear either during pregnancy or in the postpartum period. In this case report, we present a non-hemophiliac patient, who presented five months postpartum with intermittent heavy vaginal bleeding, easy bruising, hemarthrosis, and recurrent frank hematuria. The woman presented to the emergency room with hematuria. Coagulation screening tests showed a prolonged APTT. Using a standard diagnostic algorithm, a Factor VIII inhibitor was detected. The treatment, cause of disease, and prognosis of this woman is presented in this paper as well as a literature review of acquired hemophilia A associated with pregnancy. Resume : Des anticorps contre Ie facteur VIII (FVIII) peuvent apparaitre chez des patientes non hemophiles et causer une maladie rare, I'hemophilie acquise. Chez 7,3 % de ces patientes, les inhibiteurs du FVIII apparaissent soit pendant la grossesse, so it pendant Ie postpartum. Cette etude de cas porte sur une patiente non hemophile qui, au cinquieme mois du postpartum, presentait une saignement vaginal abondant, une predisposition aux ecchymoses, une hemarthrose et une hematurie visible et recurrente. Cette patiente s'est presentee it I'urgence en raison d'une hematurie. Les tests de depistage des troubles de coagulation ont revele un TCA prolonge. Un algorithme de diagnostic normal a permis de deceler la presence d'un inhibiteur du FVIII. Cet article presente Ie traitement, la cause de la maladie et Ie pronostic de cette patiente et passe en revue les publications medicales sur I'hemophilie A acquise Iiee it la grossesse.
J Obstet
CASE REPORT
Wendy (pseudonym) is a 25-year-old woman who gave birth to her second child in May 1997. Labour was uneventful. A healthy 3400 g baby girl was born by normal vaginal delivery. Wendy was discharged from hospital two days later (the usual time period for this hospital). Wendy noticed more vaginal bleeding than she recalled occurring during the first two weeks after the birth of her first baby, but she did not seek any medical attention as she thought this was probably normal after a second baby. Wendy described the bleeding as heavy, requiring pad change every two hours and double protection for five months postpartum. The vaginal bleeding became intermittent but continued to be heavy, stopping only for a few days every two to three weeks. Wendy also reported bruising extensively after only trivial trauma to her foot. A week later, she noticed hematuria, which lasted for five days, and she then sought medical advice. Wendy's family physician investigated and excluded urinary tract infection or renal calculi. Blood work, including an APTT, was requested. The APTT was significantly prolonged. The regional coagulation laboratory used a diagnostic algorithm. Initial investigation suggested an inhibitor to Factor VIII (FVIII) was present. FVIII Bethesda assays confirmed the presence of an inhibitor to FYI!I. The results of the blood work were as follows. Hemoglobin: 134 gil (120-160 gil) Platelet count: 2.69 x 10 12 (1.30-4.00 X 10 12) APTT: 82.5 sec (23.9-35.7 sec.) FVIII:C: <0.01 U/mL (0.50-1.50 U) Inhibitor: 67.0 Bethesda Units (BU) (0.0-0.0 BU).
Gynaecol Can 2002;24(5):430-2.
KeyWords Recombinant FVlla, postpartum hemorrhage, acquired hemophilia, FVIII inhibitor Competing interests: None declared. Received on October 16. 200 I Revised and accepted on December 5. 200 I
Wendy was referred to a hematologist for consultation and was diagnosed with acquired hemophilia. All therapeutic options were discussed with Wendy, including the use of rFVIIa, which was not available in the province and was ordered through the special access program to have on hand in case of a major bleeding episode. Wendy was prescribed prednisone (1 mg/kg/day). A few days later, she presented to the
jOGC.
MAY 2002
Emergency Room with a major forearm hematoma and early compartment syndrome. Wendy was admitted to the hospital under the care of the hematologist, and received an initial rFVIIa IV bolus of90 l1g/kg every 2 hours for 7 doses. This treatment was continued with longer intervals (3-6 hours) for the next two days under close clinical supervision. She was discharged after 5 days when the inhibitor level had dropped to 50% of her admission level and bleeding was controlled. A few weeks later, Wendy re-presented to the Emergency Room with severe knee pain. There was no evidence of bleeding and she was diagnosed to have a steroid myopathy, which was treated with pain relief and exercise. Wendy's rFVIIIa inhibitor level was decreasing so her prednisone dosage was tapered in early December. Wendy then had an episode of puncture site bleeding after routine blood work, which was treated with an increase in prednisone and another 4 doses of rFVIIa. Wendy developed glucocorticoid-related complications of weight gain (24.5 kg), acne, hirsutism, and psychological changes (mood swings and depression). She also developed areas of alopecia on her scalp. Wendy was started on immunoglobulin therapy while tapering her prednisone, but this did not appear to alter her inhibitor levels. Cyclosporine was also administered but discontinued after 5 days as Wendy tolerated it poorly. Wendy presented to the Emergency Room for the third time on January 12, 1998, because of another episode of severe hematuria, again with severe joint pains in her knees, ankles, and hips. She was again admitted to hospital and started on rFVIIa to control the bleeding episode. Wendy improved gradually and did not report any further bleeding episodes. She was monitored continuously throughout her illness by factor and inhibitor assays. The inhibitor disappeared from her circulation 14 months from the time of diagnosis. Wendy returned to her normal weight and has remained well since. HEMOPHIUA A AND PREGNANCY
When inhibitors to FVIII are encountered in non-hemophiliac patients, the disorder is termed hemophilia A. The incidence of acquired hemophilia has been estimated to be 1 per year per 0.5-1 million people.! The management of patients who develop Factor VIII inhibitors during the puerperium is a complex medical and economic challenge. Inhibitors can appear at any time between 3 days to 7 months after normal labour. Usually, there is no association with any underlying autoimmune disease. When associated with pregnancy, the clinical presentation occurs within 3 months of delivery as extensive bruising, genitourinary tract bleeding, hemarthrosis, or as life-threatening hemorrhage. Delayed postpartum hemorrhage can be the first presenting symptom requiring medical attention. The diagnosis of this rare illness can be missed if an appro-
priate laboratory diagnostic algorithm is not used to ascertain the cause of the prolonged APTT. It is important for obstetricians and primary care physicians to consider medical as well as obstetrical causes of postpartum bleeding. Epidemiological studies 2.3 suggest that 1-2% of the population has a hereditary bleeding tendency and that the vast majority of these patients are undiagnosed. A careful clinical history is most important to make an accurate diagnosis. Characteristically, patients with hereditary bleeding disorders complain of increased menstrual flow from menarche, easy bruising, and epistaxsis. In contrast, patients with acquired inhibitors have new onset bleeding symptoms. It is recommended that patients who acquire hemophilia be managed using a team approach, including an obstetrician and a hematologist involved in a regional hemophilia comprehensive care program. The autoantibodies against FVIII are identified predominantly in adults. The major peak incidence is seen in patients over the age of 50,4 while the second peak is in peripartum women. 4 It is estimated that 7.3% of these cases occur during pregnancy or in the postpartum period. 4 Serious bleeding was reported in 87% of patients with FVIII inhibitors, and in up to 22% of these, the bleeding episode was fata\.4 The best screening coagulation test is the APTT. Correction studies (50:50 mix) do not correct the prolongation, as typically the APTT is more prolonged after incubation for 60 minutes. The diagnosis is confirmed by measuring FVIII levels. The inhibitor titre is measured by using the Bethesda assay. Treatment options focus on eliminating the inhibitor and controlling bleeding. Due to the rarity of the disorder, therapeutic options reported in the literature are anecdotal and descriptive. 4,S.G The therapeutic options to eliminate the inhibitor include steroids, immunoglobulins, and immunosuppressive agents such as cyclosporine, cyclophosphamide, azathiopurine, and a combination of these therapies. G,7 The Association of Hemophilia Clinic Directors of Canada (AHCDC) guidelines7 for 1999 recommended that patients with acquired hemophilia presenting with bleeding - considered to be neither life- nor limb-threatening - should start with 1 mg/kg/ day prednisone for three weeks or until elimination of inhibitors. Immunoglobulins (lVIG) may also be given in a dose of 0.4 g/kg/day. Desmopressin (DDAVP), as a hemostatic therapy, may be used to control bleeding. It is given in a dose of 0.3 mg/kg IV or SC, to a maximum dose of 20 mg. It is also available as an intranasal spray (150 mg!puff/nostril). Porcine FVIII 50-100 IU/kg can be tried if desmopressin fails. Recombinant Factor VIla (rFVIIa) as a 70-90 mg/kg bolus at every 2 hours should be considered to control bleeding. In cases of mild bleeding, one or two doses may be sufficient. In life- or limb-threatening bleeding, porcine FVIII or rFVlIa should be considered for first-line therapy. Immunosuppressive drugs are contraindicated during pregnancy and lactation'? In our patient, rFVIIa was clinically useful to achieve control of Wendy's bleeding episodes.
jOGC.
MAY 2002
DISCUSSION
CONCLUSION
It is essential to consider medical and obstetrical diagnoses in the differential diagnosis for postpartum hemorrhage. A careful history is helpful to differentiate congenital and acquired bleeding disorders. Screening coagulation assays should include a CBC, PT, APTT, fibrinogen, and bleeding or closure time. Characteristically, patients who develop an acquired inhibitor present with acute bleeding problems, which may be life-threatening. The APTT is prolonged. The diagnosis of acquired hemophilia A must be confirmed by measuring FVIII activity and FVIII inhibitor levels. Early diagnosis and rapid decisionmaking may save the patient from unnecessary and potentially dangerous surgical interventions to stop bleeding. Inhibitors to FVIII in 15-25% of hemophilia A patients may develop during the course of FVIII replacement treatment. 5,8,9 The etiology of inhibitor development in the puerperium is unknown. Once these antibodies are identified, therapeutic strategies are directed towards achieving adequate hemostasis and decreasing the inhibitor levels. Treatment options to control bleeding include prothrombin complex concentrates, DDAVp, anti-fibrinolytic therapy, high-dose FVIII with or without immunosuppressive drugs, porcine FVIII, and rFVIIa. In pharmacological dosage, rFVIIa binds to circulating tissue factor (TF) at the site of injury to activate factor Xa and initiate the coagulation cascade independently ofFVIII. 8,9 Recombinant Factor rFVIIa is produced in baby hamster kidney cells. The sophisticated fermentation, purification, and formulation steps of the manufacturing process leave the product safe, free of cells, free of albumin, and hence free of any risk of viral transmission. lO Factor rFVIIa should be administered in a dose of 70-90 jlg/kg, every two hours for 4-6 doses as needed (in mild bleeding, 1 or 2 doses may suffice). Should the clinical response indicate administration of more rFVIIa, then the interval between the subsequent doses should be longer. In most cases, prednisone at 1 mg/kg/day, as an immunosuppressive therapy, is recommended for three weeks or until elimination of the inhibitor. Immunoglobulins (IVIG) may also be given concurrently with prednisone in a dose of 0.4 glkglday for 5 consecutive days. Other immunosuppressive medications, such as cyclophosphamide or azathioprine in a dose of 1.5 mg/kg/day (max. 100 mg/day) for 8-12 weeks, can be considered to eradicate the inhibitor. Even if these immunosuppressives do not induce complete remission, they may slightly reduce the time needed for that remission to occur. 11 However, immunosuppressive drugs are contraindicated during pregnancy and for nursing mothers. In postpartum patients, inhibitors almost always resolve spontaneously, usually within 30 months.7,l1 Therefore, one can argue that for a conservative approach to immunosuppressive therapy, given the expected good outcome, especially during pregnancy, rFVIIa is a good therapeutic choice for bleeding episodes because of its efficacy and safety.
Medical diagnoses including congenital and acquired bleeding disorders, such as acquired hemophilia A, should be considered in all cases of unexplained postpartum hemorrhage prior to any surgical interventions. rFVIIa is safe, effective, and has no risk of infectious disease transmission. It can be a life-saving treatment during severe bleeding episodes in patients who acquire hemophilia. Treatment may last months before achieving complete eradication of inhibitors. Spontaneous remission usually occurs within 30 months. Recurrence in consequent pregnancies is documented. Use of steroids and immunosuppressive drugs is based on anecdotal evidence only and remains controversial. ACKN~DGEMENTS
The authors would like to acknowledge two individuals who have helped in the care of this patient: Charlotte Sheppard, the nurse coordinator, and Michelle Hendry, the chief lab technologist at Newfoundland Health Sciences Centre, Memorial University. REFERENCES Hoyler LW.Acquired anticoagulants. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, editors. Williams hematology. 5th ed. New York: McGraw-Hili; 1995. p. 1485-96. 2. Rodeghiero F. Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease, Blood 1987;69(2):454-9. 3. Werner EJ, Broxton EH,Tucker EL, Giroux DL, Shultz J,Abshire TC. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 1993; 123:893-8. 4. Green D, Lechner K.A survey of 215 non-hemophiliac patients with inhibitors to FVIII. Thromb Haemost 1981 ;45(3):200-3. 5. Hedner U. Recombinant coagulation FactorVlla:from the concept to clinical application in hemophilia treatment in 2000. Seminars in Thrombosis and Hemostasis 2000;26(4):363-6. 6. Saxena R, Mishra DK, Kashyap R, ChoudaryVp, Mahapatra M, Bhargava M.Acquired haemophilia: a study of ten cases. Haemophilia 2000;6(2):78-83. 7. Rubinger M, Rivard GE,Teitel J,Walker I. Suggestions for the management of hemophiliacs and non-hemophiliacs with FactorVl1i inhibitors. 3rd ed.The Association of Hemophilia Clinic Directors of Canada (AHCDC); 1999. 8. Kaufman Rj,Antonarakis SE, Fray PJ. FactorVll1 and haemophiliaA In: Colman RW, Hirsh J, MarderVJ, Clowes AW, George IN, editors. Haemostasis and thrombosis, basic principles and clinical practice, Philadelphia: Lippincott,Williams &Wilkins; 2000. p. 135-5 I. 9. Burrows RF. Haemorrhagic complications in obstetric patients. In: Colman RW, Hirsh J, MarderVJ, Clowes AW, George IN, editors. Haemostasis and thrombosis, basic principles and clinical practice. Philadelphia: Lippincott, Williams & Wilkins; 2000. p. 1045-5 I. 10. Safe and effective choice for treatment of hemophilia, recombinant products. Toronto: Core Health Services Inc.; 1999. II. Michiels JJ, Hamulyak K, Nieuwenhuis HK, Novakova I, van Vliet HH. Acquired haemophilia A in women postpartum: management of bleeding episodes and natural history of FactorVll1 inhibitor. Eur J Haematol 1997;59: I05-9.
jOGc.
I.
MAY 2002
Abstract: Antibodies against Factor VIII (FVIII) can develop in non-hemophiliac patients, causing the rare condition of acquired hemophilia. In 7.3% of the patients, the FVIII inhibitors appear either during pregnancy or in the postpartum period. In this case report, we present a non-hemophiliac patient, who presented five months postpartum with intermittent heavy vaginal bleeding, easy bruising, hemarthrosis, and recurrent frank hematuria. The woman presented to the emergency room with hematuria. Coagulation screening tests showed a prolonged APTT. Using a standard diagnostic algorithm, a Factor VIII inhibitor was detected. The treatment, cause of disease, and prognosis of this woman is presented in this paper as well as a literature review of acquired hemophilia A associated with pregnancy. Resume : Des anticorps contre Ie facteur VIII (FVIII) peuvent apparaitre chez des patientes non hemophiles et causer une maladie rare, I'hemophilie acquise. Chez 7,3 % de ces patientes, les inhibiteurs du FVIII apparaissent soit pendant la grossesse, so it pendant Ie postpartum. Cette etude de cas porte sur une patiente non hemophile qui, au cinquieme mois du postpartum, presentait une saignement vaginal abondant, une predisposition aux ecchymoses, une hemarthrose et une hematurie visible et recurrente. Cette patiente s'est presentee it I'urgence en raison d'une hematurie. Les tests de depistage des troubles de coagulation ont revele un TCA prolonge. Un algorithme de diagnostic normal a permis de deceler la presence d'un inhibiteur du FVIII. Cet article presente Ie traitement, la cause de la maladie et Ie pronostic de cette patiente et passe en revue les publications medicales sur I'hemophilie A acquise Iiee it la grossesse.
J Obstet
CASE REPORT
Wendy (pseudonym) is a 25-year-old woman who gave birth to her second child in May 1997. Labour was uneventful. A healthy 3400 g baby girl was born by normal vaginal delivery. Wendy was discharged from hospital two days later (the usual time period for this hospital). Wendy noticed more vaginal bleeding than she recalled occurring during the first two weeks after the birth of her first baby, but she did not seek any medical attention as she thought this was probably normal after a second baby. Wendy described the bleeding as heavy, requiring pad change every two hours and double protection for five months postpartum. The vaginal bleeding became intermittent but continued to be heavy, stopping only for a few days every two to three weeks. Wendy also reported bruising extensively after only trivial trauma to her foot. A week later, she noticed hematuria, which lasted for five days, and she then sought medical advice. Wendy's family physician investigated and excluded urinary tract infection or renal calculi. Blood work, including an APTT, was requested. The APTT was significantly prolonged. The regional coagulation laboratory used a diagnostic algorithm. Initial investigation suggested an inhibitor to Factor VIII (FVIII) was present. FVIII Bethesda assays confirmed the presence of an inhibitor to FYI!I. The results of the blood work were as follows. Hemoglobin: 134 gil (120-160 gil) Platelet count: 2.69 x 10 12 (1.30-4.00 X 10 12) APTT: 82.5 sec (23.9-35.7 sec.) FVIII:C: <0.01 U/mL (0.50-1.50 U) Inhibitor: 67.0 Bethesda Units (BU) (0.0-0.0 BU).
Gynaecol Can 2002;24(5):430-2.
KeyWords Recombinant FVlla, postpartum hemorrhage, acquired hemophilia, FVIII inhibitor Competing interests: None declared. Received on October 16. 200 I Revised and accepted on December 5. 200 I
Wendy was referred to a hematologist for consultation and was diagnosed with acquired hemophilia. All therapeutic options were discussed with Wendy, including the use of rFVIIa, which was not available in the province and was ordered through the special access program to have on hand in case of a major bleeding episode. Wendy was prescribed prednisone (1 mg/kg/day). A few days later, she presented to the
jOGC.
MAY 2002
Emergency Room with a major forearm hematoma and early compartment syndrome. Wendy was admitted to the hospital under the care of the hematologist, and received an initial rFVIIa IV bolus of90 l1g/kg every 2 hours for 7 doses. This treatment was continued with longer intervals (3-6 hours) for the next two days under close clinical supervision. She was discharged after 5 days when the inhibitor level had dropped to 50% of her admission level and bleeding was controlled. A few weeks later, Wendy re-presented to the Emergency Room with severe knee pain. There was no evidence of bleeding and she was diagnosed to have a steroid myopathy, which was treated with pain relief and exercise. Wendy's rFVIIIa inhibitor level was decreasing so her prednisone dosage was tapered in early December. Wendy then had an episode of puncture site bleeding after routine blood work, which was treated with an increase in prednisone and another 4 doses of rFVIIa. Wendy developed glucocorticoid-related complications of weight gain (24.5 kg), acne, hirsutism, and psychological changes (mood swings and depression). She also developed areas of alopecia on her scalp. Wendy was started on immunoglobulin therapy while tapering her prednisone, but this did not appear to alter her inhibitor levels. Cyclosporine was also administered but discontinued after 5 days as Wendy tolerated it poorly. Wendy presented to the Emergency Room for the third time on January 12, 1998, because of another episode of severe hematuria, again with severe joint pains in her knees, ankles, and hips. She was again admitted to hospital and started on rFVIIa to control the bleeding episode. Wendy improved gradually and did not report any further bleeding episodes. She was monitored continuously throughout her illness by factor and inhibitor assays. The inhibitor disappeared from her circulation 14 months from the time of diagnosis. Wendy returned to her normal weight and has remained well since. HEMOPHIUA A AND PREGNANCY
When inhibitors to FVIII are encountered in non-hemophiliac patients, the disorder is termed hemophilia A. The incidence of acquired hemophilia has been estimated to be 1 per year per 0.5-1 million people.! The management of patients who develop Factor VIII inhibitors during the puerperium is a complex medical and economic challenge. Inhibitors can appear at any time between 3 days to 7 months after normal labour. Usually, there is no association with any underlying autoimmune disease. When associated with pregnancy, the clinical presentation occurs within 3 months of delivery as extensive bruising, genitourinary tract bleeding, hemarthrosis, or as life-threatening hemorrhage. Delayed postpartum hemorrhage can be the first presenting symptom requiring medical attention. The diagnosis of this rare illness can be missed if an appro-
priate laboratory diagnostic algorithm is not used to ascertain the cause of the prolonged APTT. It is important for obstetricians and primary care physicians to consider medical as well as obstetrical causes of postpartum bleeding. Epidemiological studies 2.3 suggest that 1-2% of the population has a hereditary bleeding tendency and that the vast majority of these patients are undiagnosed. A careful clinical history is most important to make an accurate diagnosis. Characteristically, patients with hereditary bleeding disorders complain of increased menstrual flow from menarche, easy bruising, and epistaxsis. In contrast, patients with acquired inhibitors have new onset bleeding symptoms. It is recommended that patients who acquire hemophilia be managed using a team approach, including an obstetrician and a hematologist involved in a regional hemophilia comprehensive care program. The autoantibodies against FVIII are identified predominantly in adults. The major peak incidence is seen in patients over the age of 50,4 while the second peak is in peripartum women. 4 It is estimated that 7.3% of these cases occur during pregnancy or in the postpartum period. 4 Serious bleeding was reported in 87% of patients with FVIII inhibitors, and in up to 22% of these, the bleeding episode was fata\.4 The best screening coagulation test is the APTT. Correction studies (50:50 mix) do not correct the prolongation, as typically the APTT is more prolonged after incubation for 60 minutes. The diagnosis is confirmed by measuring FVIII levels. The inhibitor titre is measured by using the Bethesda assay. Treatment options focus on eliminating the inhibitor and controlling bleeding. Due to the rarity of the disorder, therapeutic options reported in the literature are anecdotal and descriptive. 4,S.G The therapeutic options to eliminate the inhibitor include steroids, immunoglobulins, and immunosuppressive agents such as cyclosporine, cyclophosphamide, azathiopurine, and a combination of these therapies. G,7 The Association of Hemophilia Clinic Directors of Canada (AHCDC) guidelines7 for 1999 recommended that patients with acquired hemophilia presenting with bleeding - considered to be neither life- nor limb-threatening - should start with 1 mg/kg/ day prednisone for three weeks or until elimination of inhibitors. Immunoglobulins (lVIG) may also be given in a dose of 0.4 g/kg/day. Desmopressin (DDAVP), as a hemostatic therapy, may be used to control bleeding. It is given in a dose of 0.3 mg/kg IV or SC, to a maximum dose of 20 mg. It is also available as an intranasal spray (150 mg!puff/nostril). Porcine FVIII 50-100 IU/kg can be tried if desmopressin fails. Recombinant Factor VIla (rFVIIa) as a 70-90 mg/kg bolus at every 2 hours should be considered to control bleeding. In cases of mild bleeding, one or two doses may be sufficient. In life- or limb-threatening bleeding, porcine FVIII or rFVlIa should be considered for first-line therapy. Immunosuppressive drugs are contraindicated during pregnancy and lactation'? In our patient, rFVIIa was clinically useful to achieve control of Wendy's bleeding episodes.
jOGC.
MAY 2002
DISCUSSION
CONCLUSION
It is essential to consider medical and obstetrical diagnoses in the differential diagnosis for postpartum hemorrhage. A careful history is helpful to differentiate congenital and acquired bleeding disorders. Screening coagulation assays should include a CBC, PT, APTT, fibrinogen, and bleeding or closure time. Characteristically, patients who develop an acquired inhibitor present with acute bleeding problems, which may be life-threatening. The APTT is prolonged. The diagnosis of acquired hemophilia A must be confirmed by measuring FVIII activity and FVIII inhibitor levels. Early diagnosis and rapid decisionmaking may save the patient from unnecessary and potentially dangerous surgical interventions to stop bleeding. Inhibitors to FVIII in 15-25% of hemophilia A patients may develop during the course of FVIII replacement treatment. 5,8,9 The etiology of inhibitor development in the puerperium is unknown. Once these antibodies are identified, therapeutic strategies are directed towards achieving adequate hemostasis and decreasing the inhibitor levels. Treatment options to control bleeding include prothrombin complex concentrates, DDAVp, anti-fibrinolytic therapy, high-dose FVIII with or without immunosuppressive drugs, porcine FVIII, and rFVIIa. In pharmacological dosage, rFVIIa binds to circulating tissue factor (TF) at the site of injury to activate factor Xa and initiate the coagulation cascade independently ofFVIII. 8,9 Recombinant Factor rFVIIa is produced in baby hamster kidney cells. The sophisticated fermentation, purification, and formulation steps of the manufacturing process leave the product safe, free of cells, free of albumin, and hence free of any risk of viral transmission. lO Factor rFVIIa should be administered in a dose of 70-90 jlg/kg, every two hours for 4-6 doses as needed (in mild bleeding, 1 or 2 doses may suffice). Should the clinical response indicate administration of more rFVIIa, then the interval between the subsequent doses should be longer. In most cases, prednisone at 1 mg/kg/day, as an immunosuppressive therapy, is recommended for three weeks or until elimination of the inhibitor. Immunoglobulins (IVIG) may also be given concurrently with prednisone in a dose of 0.4 glkglday for 5 consecutive days. Other immunosuppressive medications, such as cyclophosphamide or azathioprine in a dose of 1.5 mg/kg/day (max. 100 mg/day) for 8-12 weeks, can be considered to eradicate the inhibitor. Even if these immunosuppressives do not induce complete remission, they may slightly reduce the time needed for that remission to occur. 11 However, immunosuppressive drugs are contraindicated during pregnancy and for nursing mothers. In postpartum patients, inhibitors almost always resolve spontaneously, usually within 30 months.7,l1 Therefore, one can argue that for a conservative approach to immunosuppressive therapy, given the expected good outcome, especially during pregnancy, rFVIIa is a good therapeutic choice for bleeding episodes because of its efficacy and safety.
Medical diagnoses including congenital and acquired bleeding disorders, such as acquired hemophilia A, should be considered in all cases of unexplained postpartum hemorrhage prior to any surgical interventions. rFVIIa is safe, effective, and has no risk of infectious disease transmission. It can be a life-saving treatment during severe bleeding episodes in patients who acquire hemophilia. Treatment may last months before achieving complete eradication of inhibitors. Spontaneous remission usually occurs within 30 months. Recurrence in consequent pregnancies is documented. Use of steroids and immunosuppressive drugs is based on anecdotal evidence only and remains controversial. ACKN~DGEMENTS
The authors would like to acknowledge two individuals who have helped in the care of this patient: Charlotte Sheppard, the nurse coordinator, and Michelle Hendry, the chief lab technologist at Newfoundland Health Sciences Centre, Memorial University. REFERENCES Hoyler LW.Acquired anticoagulants. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, editors. Williams hematology. 5th ed. New York: McGraw-Hili; 1995. p. 1485-96. 2. Rodeghiero F. Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease, Blood 1987;69(2):454-9. 3. Werner EJ, Broxton EH,Tucker EL, Giroux DL, Shultz J,Abshire TC. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 1993; 123:893-8. 4. Green D, Lechner K.A survey of 215 non-hemophiliac patients with inhibitors to FVIII. Thromb Haemost 1981 ;45(3):200-3. 5. Hedner U. Recombinant coagulation FactorVlla:from the concept to clinical application in hemophilia treatment in 2000. Seminars in Thrombosis and Hemostasis 2000;26(4):363-6. 6. Saxena R, Mishra DK, Kashyap R, ChoudaryVp, Mahapatra M, Bhargava M.Acquired haemophilia: a study of ten cases. Haemophilia 2000;6(2):78-83. 7. Rubinger M, Rivard GE,Teitel J,Walker I. Suggestions for the management of hemophiliacs and non-hemophiliacs with FactorVl1i inhibitors. 3rd ed.The Association of Hemophilia Clinic Directors of Canada (AHCDC); 1999. 8. Kaufman Rj,Antonarakis SE, Fray PJ. FactorVll1 and haemophiliaA In: Colman RW, Hirsh J, MarderVJ, Clowes AW, George IN, editors. Haemostasis and thrombosis, basic principles and clinical practice, Philadelphia: Lippincott,Williams &Wilkins; 2000. p. 135-5 I. 9. Burrows RF. Haemorrhagic complications in obstetric patients. In: Colman RW, Hirsh J, MarderVJ, Clowes AW, George IN, editors. Haemostasis and thrombosis, basic principles and clinical practice. Philadelphia: Lippincott, Williams & Wilkins; 2000. p. 1045-5 I. 10. Safe and effective choice for treatment of hemophilia, recombinant products. Toronto: Core Health Services Inc.; 1999. II. Michiels JJ, Hamulyak K, Nieuwenhuis HK, Novakova I, van Vliet HH. Acquired haemophilia A in women postpartum: management of bleeding episodes and natural history of FactorVll1 inhibitor. Eur J Haematol 1997;59: I05-9.
jOGc.
I.
MAY 2002