Acquired haemophilia syndrome: pathophysiology and therapy

Abstract

Acquired inhibitors against coagulation factor VIII (FVIII), also termed acquired haemophilia A, neutralize its procoagulant function and result in severe or often life-threatening bleeding. The antibodies arise in individuals with no prior history of clinical bleeding. Acquired haemophilia occurs rarely with the incidence of approximately 1 to 4 per million/year, with severe bleeds in up to 90% of affected patients, and high mortality between 8-22%. About 50% of diagnosed patients were previously healthy, while the remaining cases may be associated with postpartum period, autoimmune diseases, malignancy, infections, or medications. Most patients have spontaneous haemorrhages into the skin, muscles or soft tissues, and mucous membranes, or after trauma and surgery, whereas haemarthroses are uncommon. The diagnosis of acquired haemophilia A based on the prolongation of activated partial thromboplastin time which does not normalize after the addition of normal plasma, reduced FVIII, with evidence of FVIII inhibitor measured by the Bethesda assay (Nijmegen modification). The treatment of acute bleeding episodes and the long-term eradication of the autoantibodies in acquired haemophilia are the main therapeutic strategy. Two options are currently available for acute bleeding control: the use rFVIIa or FEIBA in patients with higher inhibitor titer (> 5 BU), or to raise the level of FVIII by administration of DDAVP or concentrates of FVIII in patients with low level of inhibitors (< 5 BU). Treatment with FEIBA (50-100 IU/ kg every 8-12 hours) has shown good haemostatic response in 76-89% of the bleeding episodes. Patients treated with rFVIIa (90 microg/kg every 2-6 hours) have achieved good response in 95-100% as a first-line, and 75-80% as a salvage therapy. Patients with low inhibitor titer and lower response can be treated with concentrate of FVIII in the recommended dose of 40 IU/kg plus 20 IU/kg for each BU of inhibitor. The treatment of non-life-threatening haemorrhages with desmopressin (DDAVP 0.3 microg/kg) may increase both FVIII and vWF. Sometimes inhibitors disappear spontaneously, but long-term management is necessary for eradication of inhibitors by immunosuppression (prednisone 1 mg/kg 3 weeks alone or in combination cyclophosphamide 2 mg/kg), immunomodulation, intravenous immunoglobulin (HD IgG 2 g/kg 2 or 5 d), physical removal of antibodies (plasmapheresis or immunoadsorption), or various combinations. Recently, a therapy with rituximab, an anti-CD20 monoclonal antibody, has shown to be effective in acquired haemophilia.