Acquired hemophilia A may be associated with itraconazole

Abstract

Acquired hemophilia A is a rare disorder, with an annual occurrence rate of 1.48 cases per million [1], caused by autoantibodies against coagulation factor VIII (FVIII) [2].These autoantibodies mainly affect elderly patients and are often present without any underlying disease, but may occur in various conditions such as pregnancy, autoimmune disorders, solid tumors, and lymphoproliferative syndromes. Several drugs, such as penicillin and its derivatives, phenytoin, and sulfa drugs, have also been reported to be associated with antibodies to FVIII [3]. Collins et al. [1] reported the results of a 2-year national study of acquired hemophilia A performed by the UK Haemophilia Centre Doctors’ Organisation; the results of this study indicated that diagnosis of underlying disorders associated with acquired hemophilia A was very difficult, especially in old age (patients between 60 and 79 years, 42%; those aged 80 or over, 23%). Here, we report a 74year-old case of acquired hemophilia A associated with itraconazole. A 74-year-old woman was admitted to our hospital with a 3-week history of peripheral edema, palpable purpura, and arthritis. There was no previous personal or family history of bleeding. She also had no past history of illness until 4 weeks before admission, but she took 200 mg/day of itraconazole because of tinea pedis for 4 weeks before admission. On examination, the results of laboratory work-up were as follows: hemoglobin level, 5.7 g/dl; platelet count, 324 9 10 ml; white blood cell count, 9.3 9 10 ml; prothrombin time, 91% (normal 80–120%); activated partial thromboplastin time (APTT), 80.3 s (normal 25–39 s). Tests for lupus anticoagulant, anticardiolipin antibody, antinuclear factor, double stranded DNA, and rheumatoid factor were negative. Fiberscopy examination revealed esophageal ulcer as the reason for the anemia. Remarkably prolonged APTT (166.5 s) and huge iliopsoas hematoma appeared 15 days after admission. The levels of FVIII activity (FVIII:C) and FVIII-inhibitory activity on admission were \1% and 23 Bethesda units, respectively, thus confirming the presence of acquired FVIII inhibitor. The levels of von Willebrand factor (VWF) antigen (VWF:Ag) and VWF-inhibitory activity were prepared to be examined when the levels of FVIII:C were low and FVIII-inhibitory activity was negative. A diagnosis of acquired hemophilia A was made and the patient was treated with activated prothrombin complex concentrate (APCC); 1500 units every 12 h in addition to 50 mg/day of cyclophosphamide and 1 mg/kg of prednisolone. Her iliopsoas hematoma was effectively controlled with no subsequent recurrence. APCC was discontinued after 3 days. Cyclophosphamide and prednisolone were continued with slow tapering, and FVIII inhibitor became undetectable after 10 weeks, and FVIII:C level got normalized after 18 weeks. In spite of additional examination of another underlying disease, none of autoimmune disorders, solid tumors, and lymphoproliferative syndromes were detected. A possible link between autoimmune acquired hemophilia and itraconazole has not been previously reported. Itraconazole has been associated with neutropenia [4], suggesting other possible immune mediated adverse events. This patient could be cured because of the rapid diagnosis. Investigation of FVIII:C and FVIII-inhibitory H. Tamai S. Tanosaki Department of Hematology, The Fraternity Memorial Hospital, Tokyo, Japan