A 23-year-old 500-kg (1,100-lb) Thoroughbred mare with a large mass (which was presumed to be a hematoma) located on the right ventral flank was referred to the Steinbeck Country Equine Clinic. Nine days before referral, the mare was examined by a primary-care veterinarian because of a large swelling on the right lateral abdominal region that extended from just caudal to the last rib to the 11th intercostal space. At that time, the swelling caused signs of pain and the mare had a stiff gait in the right hind limb; however, palpation and flexion of the limb revealed no abnormalities.
The primary-care veterinarian sedated the mare and performed a per rectal examination. A firm swelling was palpable 60 cm from the rectum on the right side; this swelling was presumed to be associated with the body wall mass. A blood sample was collected for a CBC, which revealed mild anemia and lymphopenia. It was suspected that another horse had kicked the mare and that the swelling in the flank region was a large posttraumatic hematoma.
Treatment prescribed for the mare by the primary-care veterinarian included rest and phenylbutazone (4 mg/kg [1.81 mg/lb], IV, once; then 4.4 mg/kg [2 mg/lb], PO, q 12 h for 2 days; and then 2.2 mg/kg [1 mg/lb], PO, q 12 h for 2 days) and a single dose of dexamethasone (0.08 mg/kg [0.036 mg/lb], IV). The mare initially had no signs of discomfort; however, 7 days after initiation of treatment, the mare was quiet and had a decreased appetite. Two days later (9 days after initiation of treatment), the mare was tachycardic and the size of the swelling on the body wall had increased. The mare was treated with phenylbutazone (4.4 mg/kg, IV) and referred for further evaluation.
A medical history was obtained at the time of admission to the Steinbeck Country Equine Clinic. The mare was housed alone in a pasture, although horses were housed adjacent to both sides of that pasture. The mare was used for light pleasure riding. The mare had foaled once at 13 years of age, and there was no recent history of systemic illness, medication, or travel. The mare was vaccinated annually against West Nile virus, eastern and western equine encephalomyelitis viruses, tetanus, and rabies and biannually against influenza and rhinopneumonitis. The mare had been dewormed with ivermectin 9 months prior to referral and again with moxidectin 3 months prior to referral. Dental examinations were performed annually, and floating of the mare's teeth had been performed 9 months prior to referral. The owner reported that an unknown quantity of rodenticide bars containing 0.005% bromadiolone had recently been used on the property.
Physical examination revealed that the mare was quiet, alert, and responsive. The mare was tachycardic (heart rate, 60 beats/min) but had a respiratory rate (16 breaths/min) and rectal temperature (37.8°C [100°F]) within reference limits. The mare's coat was in good condition and an appropriate length for the time of year. Body condition score was 4.5 of 9, and the musculature was symmetric. There was a large, firm swelling on the right lateral abdominal region that extended from just caudal to the last rib to the 11th intercostal space, measuring approximately 25 by 30 cm in diameter. The swelling caused signs of pain. Digital pulses were evident and within anticipated limits. The limbs were palpably cool, and peripheral pulses were slightly decreased on palpation. Mucous membranes were pale and moist, and the capillary refill time was 2 seconds. Results of cardiac auscultation were unremarkable, and the jugular refill time was slightly prolonged. The right hind limb appeared stiff, and the mare was reluctant to move the limb forward. Mentation was appropriate, findings on cranial nerve examination were unremarkable, and there was no ataxia evident in the mare during walking.
Hematologic evaluation revealed anemia (PCV, 21%; reference interval, 32% to 53%; RBC count, 5.87 × 1012 RBCs/L; reference interval, 6.80 × 1012 RBCs/L to 12.90 × 1012 RBCs/L) and lymphopenia (1.02 × 103 cells/mL; reference interval, 1.50 × 103 cells/mL to 7.70 × 103 cells/mL). Biochemical analysis revealed mildly high creatine kinase activity (354 U/L; reference interval, 10 to 350 U/L) and hyperlactatemia (2.67 mmol/L; reference interval, < 2 mmol/L). Ultrasonographic examination of the swelling on the right flank revealed that the structure appeared to be a large extra-abdominal hematoma (10 cm in depth). A hematoma (6 cm in diameter) was also visible intra-abdominally and extended from just caudal to the last rib to the xiphoid. There was an excessive amount of free fluid (13 cm in depth) in the abdomen surrounding the hematoma. The free fluid had a cellular, swirling appearance and was presumed to be blood. Results for the remainder of the abdominal and thoracic ultrasonographic examinations were unremarkable. Abdominocentesis was not performed to confirm the presence of blood because of the potential risk of introducing infectious organisms.
Per rectal examination was performed, and the pelvis and reproductive tract were unremarkable. A mass (presumed to be the intra-abdominal hematoma identified during ultrasonography) was palpable on the right side protruding from the body wall into the abdominal cavity.
Differential diagnosis for the hematomas on the body wall and the hemoabdomen included coagulopathies, neoplasms, rib fracture, trauma, and vascular anomalies. A blood sample was collected and submitted for a coagulation profile. A catheter was placed in the left jugular vein, and treatment was initiated with a balanced polyionic solutiona (2 mL/kg/h [0.91 mL/lb/h]), aminocaproic acid (loading dose, 40 mg/kg [18 mg/lb], which was followed by 20 mg/kg [9.1 mg/lb], IV, q 6 h), and vitamin K1 (1 mg/kg [0.45 mg/lb], SC, q 6 h). The polyionic solution was administered to increase the circulating volume and improve delivery of oxygen to the tissues. Aminocaproic acid, an inhibitor of plasmin and plasminogen, was administered to prevent fibrinolysis and clot dissolution. Vitamin K1 was administered because of the potential exposure to bromadiolone, a second-generation 4-hydroxycourmarin derivative and vitamin K antagonist.
The mare's PCV, systemic lactate concentration, and venous blood gases were monitored. Venous blood gas analysis indicated mild metabolic acidemia (pH, 7.35; reference interval, 7.38 to 7.54) with a low mixed-venous oxygen tension (24.9 mm Hg; reference interval, 35.6 to 54.4 mm Hg). The metabolic acidosis was likely attributable to hypoperfusion, given that the lactate concentration was elevated and the Pco2 was within reference limits.
The mare was transfused with whole blood because of the progressive anemia (PCV, 11%), persistent tachycardia, low mixed-venous oxygen tension, and poor perfusion values. A Quarter Horse gelding was selected as the blood donor; blood from that horse was compatible as determined on the basis of results of major and minor cross-matching. The mare was given a dose of flunixin meglumine (1.1 mg/kg [0.5 mg/lb], IV) and transfused with 8 L of whole blood. Urticaria developed during the transfusion, and hydroxyzine (1 mg/kg [0.45 mg/lb], PO) and dexamethasone (0.04 mg/kg [0.018 mg/lb], IV) were administered. The mare tolerated the remainder of the transfusion well.
The morning after the transfusion, results for coagulation testing were available and indicated a primary coagulopathy as a cause of the bleeding. There was severe prolongation of the APTT (> 100 seconds; reference interval, 28 to 44 seconds); however, the PT was only mildly prolonged (14.3 seconds; reference interval, 9 to 12 seconds). This coagulation profile did not support a circulating vitamin K antagonist, whereas PT is a sensitive screening test of clinically important deficiencies of vitamin K–dependent coagulation factors in the extrinsic and common pathways (ie, factors II, VII, and X).1
The mare had lactate and creatinine concentrations within the respective reference limits. Because both hypovolemia and hypoxia can adversely impact renal function, urine production and creatinine concentrations were monitored. Results of urinalysis were unremarkable, except for a trace protein content (attributed to alkaline urine) and bilirubinuria (attributed to RBC dissolution).
That afternoon, the mare's PCV decreased again (9%), heart rate increased (72 beats/min), and perfusion values deteriorated. Abdominal ultrasonography revealed no new findings. Another cross-matching was performed for blood of a different Quarter Horse gelding, and an additional 8 L of whole blood was administered. The mare was treated with hydroxyzine (1 mg/kg, PO) and flunixin meglumine (1.1 mg/kg, IV) before the transfusion but developed diffuse urticaria during the transfusion, which necessitated treatment with dexamethasone (0.04 mg/kg, IV). The mare tolerated the remainder of the transfusion well. After the transfusion was completed, the mare appeared brighter and had a lower heart rate and improved perfusion values. Supportive care, including IV administration of fluids,a flunixin meglumine (0.5 mg/kg [0.23 mg/lb], IV, q 24 h), vitamin K1, and aminocaproic acid, was continued. After the mare had received treatment with vitamin K1 for 3 days, another blood sample was submitted for coagulation testing. Results indicated that the APTT remained prolonged (> 100 seconds) and was unchanged despite the administration of vitamin K1.
To further investigate the coagulopathy and cause of the persistently prolonged APTT, citrate-anticoagulated plasma samples that had been obtained from the mare before treatment on the day of admission (and stored frozen) and obtained from the mare 4 days later (after transfusion with whole blood and administration of vitamin K1) were placed in a package containing refrigerant cold packs and shipped to a university-based coagulation laboratoryb for analysis.
Coagulation screening tests (APTT and PT) and measurement of fibrinogen concentrations were performed at the coagulation laboratory with commercial reagentsc–e in an automated instrument,f as described elsewhere.2 Coagulant activities of the intrinsic factors (factors VIII, IX, XI, and XII) were measured in modified 1-stage APTT assays with a series of human congenital factor-deficient plasmas,3,g and results were reported as the percentage activity of a pooled equine plasma standard (prepared from 12 healthy horses).
Analysis of results of coagulation testing on the pretreatment sample revealed marked prolongation of clotting time for the APTT (98.1 seconds; reference interval, 45 to 61 seconds); however, the PT (13.4 seconds; reference interval, 11 to 15 seconds) and fibrinogen concentration (387 mg/dL; reference interval, 200 to 470 mg/dL) were within reference limits. Prolongation of the APTT was attributed to factor VIII deficiency (factor VIII coagulant activity, 12%) on the basis that activities of the other intrinsic pathway factors were greater than or close to the cutoff of 50% (factor IX coagulant activity, 116%; factor XI coagulant activity, 48%; and factor XII coagulant activity, 81%). Analysis of the posttransfusion sample revealed partial correction of clotting time for the APTT (75.6 seconds), an increase in factor VIII coagulant activity (29%), and no abnormal coagulant activities for factors IX (103%), XI (66%), and XII (79%).
Because the mare failed to respond to supplemental vitamin K and the coagulation laboratory found no abnormalities in results of the PT screening test and factor IX coagulant activity in the pretreatment samples, coagulopathy caused by vitamin K deficiency was ruled out. A congenital factor VIII deficiency, associated with von Willebrand disease or hemophilia A, was considered unlikely because the mare was 23 years old and had never had spontaneous hemorrhage or abnormal bleeding after dental procedures, foaling, or injections (eg, vaccinations). Moreover, hereditary factor VIII deficiency, or classic hemophilia A, is an X-linked recessive trait that almost exclusively affects males. In humans, acquired hemophilia A is recognized as an uncommon immune-mediated coagulopathy caused by inhibitory autoantibodies against factor VIII.4,5
Immunosuppressive agents are a main component of treatment for acquired hemophilia in humans; thus, the mare was administered dexamethasone (0.08 mg/kg, IV, q 24 h) as treatment for presumptive acquired hemophilia. On the third day of treatment with dexamethasone, the mare's PCV (which had been slowly increasing) decreased to 21% and the extra-abdominal hematoma on the body wall visibly increased in size. Ultrasonographic examination revealed that there was improvement in the hemoabdomen and intra-abdominal hematoma, but the extra-abdominal hematoma had increased to 12 cm in depth. It was suspected that additional hemorrhaging into the extra-abdominal hematoma had occurred as factor VIII from the fresh whole blood transfusion was depleted from the circulation. Because the mare was hemodynamically stable, we opted to maintain corticosteroid immunosuppressive treatments and to transfuse 2 U of fresh-frozen plasmah to rapidly replenish hemostatic concentrations of factor VIII. The mare tolerated the plasma transfusion well; the PCV stabilized, and the extra-abdominal hematoma slowly decreased in size.
Fourteen days after treatment with dexamethasone was initiated, the mare's factor VIII coagulant activity was within reference limits (95%). The mare was maintained on a tapering dose of dexamethasone (decreased by 25% each week), and treatment with azathioprine (3 mg/kg [1.36 mg/lb], PO, q 24 h for 30 days) was initiated. Azathioprine, an imidazole derivative of 6-mercaptopurine, inhibits cellular proliferation and reduces antibody production and lymphocyte numbers. In small animals, adverse effects of azathioprine, including bone marrow suppression, hepatitis, and gastrointestinal upset, have been reported.6,7
The mare's PCV slowly increased, and resolution of the hemoabdomen and reduction in size of the intra-abdominal and extra-abdominal hematomas were confirmed with ultrasonography. The mare was discharged to the owner 21 days after admission, with instructions to continue administration of azathioprine and the tapering dose of dexamethasone. The mare was receiving 2 immunosuppressive drugs, so a physical examination, CBC, and biochemical analysis were performed during a recheck evaluation 2 weeks after discharge. Results of physical examination performed at that time were unremarkable, and the extra-abdominal hematoma had completely resolved.
Hematologic abnormalities included mild lymphopenia (1.27 × 103 cells/mL) attributed to corticosteroid administration and a mildly high RBC distribution width (21.1%; reference interval, 17.0% to 21.0%), which may have been attributable to a regenerative response to the initial anemia.
The mare received immunosuppressive treatment for 6 weeks, with the dexamethasone dose decreased by 25% each week. Approximately 2 months after initiation of treatment (10 days after cessation of immunosuppressive treatment), a plasma sample was submitted for evaluation. The APTT was 58.3 seconds (reference range, 45 to 61 seconds), and factor VIII coagulant activity was 67%. The mare remained healthy with no signs of coagulopathy. Follow-up coagulation testing performed at approximately 3 and 7 months after discharge from the hospital revealed an APTT within the reference range (49.5 and 52.1 seconds, respectively) and sustained factor VIII coagulant activity (55% and 62%, respectively).
Plasma remaining from the initial testing (before treatment) and from 2 subsequent submissions (3 and 7 months after discharge from the hospital) was used to screen for the presence of a factor VIII inhibitor as the cause of the mare's factor VIII deficiency. The plasma was stored frozen (–50°C) at the coagulation laboratory until tested. Factor VIII inhibitory activity was quantified in a Bethesda assay.8,i Briefly, serial dilutions of heat-treated plasma from the mare were combined with pooled equine plasma obtained from clinically normal horses and incubated at 37°C. Residual factor VIII coagulant activities of the dilutions were compared with that of a control mixture (1:1) prepared from saline (0.9% NaCl) solution combined with pooled equine plasma. In this assay, the dilution of plasma from the affected mare that contained 50% residual factor VIII coagulant activity represented 1 BU of inhibitory activity/mL. The mare's pretreatment plasma sample had an inhibitory activity titer of 2.7 BUs/mL, whereas samples obtained 3 and 7 months after discharge from the hospital had titers of 0.5 and 0.4 BUs/mL, respectively. Humans with titers between 1 and 5 BUs/mL are considered to have low inhibitory antibody titers and usually respond to immunosuppression and transfusion replacement treatment, whereas titers < 1 BU/mL are not typically associated with clinical disease.9
Approximately 1 year after initial evaluation, the mare was being used for light riding and had no additional bleeding episodes. Continued biannual monitoring of factor VIII coagulant activity was scheduled to screen the mare for relapse and recurrence of factor VIII inhibition.
Discussion
The development of inhibitory alloantibodies against factor VIII has been described in dogs with hereditary hemophilia A as a consequence of transfusion with canine factor VIII in whole blood or plasma concentrates.10,11 However, to the authors’ knowledge, acquired hemophilia associated with autoantibody formation against factor VIII has not been identified in domestic animals. In humans, antibodies reactive against factor VIII are the most commonly recognized autoantibodies to a clotting factor.12 Patients with acquired hemophilia typically have signs of a severe bleeding diathesis, with spontaneous hemorrhage into the skin or muscles, hematuria, hematemesis, melena, or prolonged postpartum or postoperative bleeding.5,13–15,29
Approximately half of the cases of acquired hemophilia are considered to be idiopathic. Reported disease triggers for the remainder include pregnancy, autoimmune disorders, neoplasia, and drug treatment.5,9,13,15–17 Pregnancy is an important risk factor, accounting for up to 15% of cases. In affected women, bleeding is typically detected from 1 to 4 months after parturition.18 Autoimmune disorders associated with acquired hemophilia include rheumatoid arthritis, systemic lupus erythematosis, dermatomyositis, hyperthyroidism and autoimmune hypothyroidism, and graftversus-host disease.13,19 Underlying neoplastic conditions include common solid tumors, such as prostatic, mammary gland, and colon cancer, and hematologic disorders, including chronic and acute lymphocytic leukemia, myelodysplasia, and myelofibrosis.9,13,19 Finally, drugs associated with the development of acquired hemophilia in humans include antimicrobials (chloramphenicol, penicillin, and sulfonamides), chemotherapeutics (fludarabine and α-interferon), and neuroactive drugs (phenytoin and methyldopa).9,13,20,21
None of these underlying risk factors were apparent in the mare described here. The mare had only foaled once 10 years before the hematoma developed and had not received any medication for 3 months before the episode. Although extensive screening to detect autoantibodies in the mare was not performed, the medical history and results of physical examinations, diagnostic imaging, and clinicopathologic testing failed to reveal abnormalities suggestive of an autoimmune disorder. Similarly, there was no evidence of neoplasia, and the mare remained healthy at approximately 1 year after initiation of treatment. Because of the lack of known disease triggers, we concluded that the development of autoantibodies against factor VIII in this mare represented idiopathic acquired hemophilia A.
Treatment of acquired hemophilia A in humans is based on the severity of bleeding, inhibitory antibody titer, and presence of identifiable disease triggers. Initial efforts are directed at rapid control of active hemorrhage by increasing circulating concentrations of factor VIII and eradication of inhibitory antibodies via immunosuppressive treatment. Patients with severe, life-threatening hemorrhage and high titers for inhibitors are treated with factor VIII–bypassing products (eg, recombinant human factor VIIa) that support assembly of the coagulation complex independent of factor VIII cofactor activity.4,12,22 Patients with less severe clinical signs are typically treated with transfusion of high-dose human factor VIII concentrates and the pharmacological agent desmopressin to increase endogenous concentrations of the factor VIII– von Willebrand factor complex.12 Administration of prednisone and cyclophosphamide is considered the first-line immunosuppressive treatment for acquired hemophilia. When prednisone and cyclophosphamide are used in combination, > 60% of patients are expected to have a favorable response.4,23–25 Patients refractory to these drugs may be treated with azathioprine, cyclosporine, vincristine, or the anti–human B-cell monoclonal antibody rituximab.26–28
Treatment of the mare described here included transfusion with fresh whole blood (16 L) and fresh-frozen plasma (1.9 L) and an immunosuppressive regimen of dexamethasone and azathioprine. Azathioprine was used in combination with dexamethasone because of its corticosteroid-sparing effects, reported efficacy in humans, and safety profile in horses.6,29 Prednisolone would also have been a viable corticosteroid alternative but was not commercially available. The mare responded well, with resolution of hemorrhage and an increase in factor VIII coagulant activity to within reference limits within 2 weeks after initiation of treatment.
Fatality rates for humans with acquired hemophilia are 10% to 22%, with variation among groups on the basis of the cause of the condition.5,13,22,30,31 Positive predictors of outcome in humans include a low inhibitor titer (between 1 and 5 BUs/mL) at initial evaluation, high factor VIII activity, low transfusion requirement, absence of an underlying condition (other than pregnancy), age < 65 years, and complete remission after first-line immunosuppressive treatment.5,9 Relapse may occur in up to 10% to 20% of patients after initial eradication of the inhibitor.22 Relapses typically occur within 6 months to 1 year after cessation of immunosuppressive treatment.22 Although comparable information is not available for veterinary species, the mare described here had a low inhibitor titer of < 5 BUs/mL at initial evaluation, and factor VIII activity improved after a blood transfusion (from 12% to 29%) and dramatically improved after immunosuppressive treatment (95%). The prognosis was good for full functional recovery of the mare. Periodic monitoring for relapse was recommended.
Acquired hemophilia in the mare described here represented a unique cause of coagulopathy that should be included as a differential diagnosis in horses with sudden onset of a bleeding diathesis associated with specific prolongation of APTT. To the authors’ knowledge, acquired hemophilia has not been previously reported in horses. The mare of this report was managed successfully by implementing a diagnostic and therapeutic strategy used for humans with acquired hemophilia A.
ABBREVIATIONS
| APTT | Activated partial thromboplastin time |
| BU | Bethesda unit |
| PT | Prothrombin time |
Plasma-Lyte, Abbott Animal Health, Abbott Park, Ill.
Comparative Coagulation Section, Animal Health Diagnostic Center, Cornell University, Ithaca, NY.
Actin Fs, Dade Behring, Newark, Del.
Thromboplastin LI, Helena Diagnostics, Beaumont, Tex.
Fibrinogen, DiagnosticaStago, Parsippany, NJ.
STACompact, DiagnosticaStago, Parsippany, NJ.
Factor deficient plasmas, George King Biomedical, Overland Park, Kan.
Polymune J plasma, 950 mL/U, Plasvacc USA Inc, Templeton, Calif.
Kasper CK, L, Aronson D, et al, in Proceedings. a more uniform measurement of factor VIII inhibitors (abstr). Thromb Diath Haemorrh 1975;34:612.
References
1. Jackson CM, Esnouf MP, Lindahl TL. A critical evaluation of the prothrombin time for monitoring oral anticoagulant therapy. Pathophysiol Haemost Thromb 2003; 33: 43–51.
2. Stokol T, Erb HN, De Wilde L, et al. Evaluation of latex agglutination kits for detection of fibrin(ogen) degradation products and d-dimer in healthy horses and horses with severe colic. Vet Clin Pathol 2005; 34: 375–382.
3. Wilson EM, Holcombe SJ, Lamar A, et al. Incidence of transfusion reactions and retention of procoagulant and anticoagulant factor activities in equine plasma. J Vet Intern Med 2009; 23: 323–328.
4. Sborov DW, Rodgers GM. Acquired hemophilia A: a current review of autoantibody disease. Clin Adv Hematol Oncol 2012; 10: 19–27.
5. Webert KE. Acquired hemophilia A. Semin Thromb Hemost 2012; 38: 735–741.
6. White SD, Maxwell LK, Szabo NJ, et al. Pharmacokinetics of azathioprine following single-dose intravenous and oral administration and effects of azathioprine following chronic oral administration in horses. Am J Vet Res 2005; 66: 1578–1583.
7. Beale KM. Azathioprine for treatment of immune-mediated diseases of dogs and cats. J Am Vet Med Assoc 1988; 192: 1316–1318.
8. Torita S, Suehisa E, Kawasaki T, et al. Development of a new modified Bethesda method for coagulation inhibitors: the Osaka modified Bethesda method. Blood Coagul Fibrinolysis 2011; 22: 185–189.
9. Franchini M, Targher G, Manzato F, et al. Acquired factor VIII inhibitors in oncohematology: a systematic review. Crit Rev Oncol Hematol 2008; 66: 194–199.
10. Giles AR, Tinlin S, Hoogendoorn H, et al. Development of factor VIII:C antibodies in dogs with hemophilia (factor VIII:C deficiency). Blood 1984; 63: 451–456.
11. O'Kelley BM, Whelan MF, Brooks MB. Factor VIII inhibitors complicating treatment of postoperative bleeding in a dog with hemophilia A. J Vet Emerg Crit Care 2009; 19: 381–385.
12. Delgado J. Acquired haemophila: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121: 21–35.
13. Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981; 45: 200–203.
14. Morrison AE. Acquired haemophilia and its management. Br J Haematol 1995; 89: 231–236.
15. Horowitz HI, Fujimoto MM. Acquired hemophilia due to a circulating anticoagulant. Report of cases, with review of the literature. Am J Med 1962; 33: 501–509.
16. Margolius A Jr, Jackson DP, Ratnoff OD. Circulating anticoagulants: a study of 40 cases and review of the literature. Medicine (Baltimore) 1961; 40: 145–202.
17. Hay CR, Ludlam CA, Colvin BT, et al. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organization. Thromb Haemost 1998; 79: 762–766.
18. Michiels JJ. Acquired hemophilia in women postpartum: clinical manifestations, diagnosis and treatment. Clin Appl Throm Hemost 2000; 6: 82–86.
19. Kessler CM. Acquired factor VIII autoantibody inhibitors: current concepts and potential therapeutic strategies for the future. Haematologica 2000; 85: 57–61.
20. Bossi P, Cabane J, Ninet J, et al. Acquired hemophilia due to factor VIII inhibitors in 34 patients. Am J Med 1998; 105: 400–408.
21. Sallah S, Wan JY. Inhibitors against factor VIII associated with use of interferon alpha and fludarabine. Thrombs Haemost 2001; 86: 1119–1121.
22. Collins PW. Therapeutic challenges in acquired factor VIII deficiency. Hematology 2012; 2012: 369–374.
23. Green D. Cytotoxic suppression of acquired factor VIII:C inhibitors. Am J Med 1991; 91: 14S–19S.
24. Shaffer LG, Phillips MD. Successful treatment of acquired hemophilia with oral immunosuppressive therapy [Erratum published in Ann Intern Med 1998; 128:330]. Ann Intern Med 1997; 127: 206–209.
25. Bayer RL, Lichtman SM, Allen SL, et al. Acquired factor VIII inhibitors—successful treatment with an oral outpatient regimen. Am J Hematol 1999; 60: 70–71.
26. Söhngen D, Specker C, Bach D, et al. Acquired factor VIII inhibitors in nonhemophilic patients. Ann Hematol 1997; 74: 89–93.
27. Lian EC, Larcada AF, Chiu AY. Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor. Ann Intern Med 1989; 110: 774–778.
28. Lian EC, Villar MJ, Nov LI, et al. Acquired factor VIII inhibitor treated with cyclophosphamide, vincristine, and prednisone. Am J Hematol 2002; 69: 294–295.
29. Snow JL, Gibson LE. A pharmacological basis for the safe and effective use of azathioprine and other thiopurine drugs in dermatologic patients. J Am Acad Dermatol 1995; 32: 114–116.
30. Morrison AE, Ludlam CA, Kessler C. Use of porcine factor VIII in the treatment of patients with acquired hemophilia. Blood 1993; 81: 1513–1520.
31. Lottenberg R, Kentro T, Kitchens C. Acquired hemophilia. A natural history study of 16 patients with factor VIII inhibitors receiving little or no therapy. Arch Intern Med 1987; 147: 1077–1081.
