Acquired hemophilia A can either be idiopathic or associated with other autoimmune disorders, malignancy, the postpartum period, and the use of drugs (such as penicillin and sulfonamides).
The incidence of autoantibodies to factor VIII is 0.2 to 1 per 1 million persons per year.
Acquired hemophilia A patients usually present with spontaneous bleeding, which often is severe and life- or limb-threatening. These patients are more likely to have a more severe bleeding diathesis than patients with hemophilia A and an inhibitor.
Common bleeding sites are soft tissues, skin, and mucous membranes. In contrast to patients with congenital hemophilia A, hemarthroses, intramuscular, and central nervous system bleeding are rare.
Patients with acquired hemophilia A have a prolonged activated partial thromboplastin time (aPTT) and a normal prothrombin time (PT). The presence of a prolonged aPTT in a 1:1 mixture between patient and normal plasma establishes the diagnosis of a circulating anticoagulant. Specific assays for factor VIII activity and/or antigen will confirm the diagnosis.
Once the identity of an inhibitor has been established, its titer is determined using the Bethesda assay. The inhibitor titer is defined as the dilution of patient plasma that produces 50% inhibition of the factor VIII activity and is expressed as Bethesda units per mL (BU/mL). Inhibitors are classified as low titer or high titer when the titers are less than 5 BU/mL or greater than 5 BU/mL, respectively.
Acquired factor VIII inhibitors sometimes resolve spontaneously. However, it is not possible to predict in which subset of patients this will occur, and so treatment will be required when bleeding complications ensue.
Patients with a factor VIII inhibitor titer of less than 5 BU/mL often are treated successfully with sufficient doses of recombinant or plasma-derived factor VIII concentrates to neutralize the inhibitor. Patients with titers between 5 and 10 BU/mL also may respond to factor VIII concentrates, whereas those with titers greater than 10 BU/mL generally do not respond.
Factor VIII bypassing agents, which drive the coagulation mechanism through the extrinsic pathway, are the mainstays of management of patients with a high titer of an inhibitor. Two agents, recombinant activated factor VII and plasma-derived factor eight-inhibitor bypassing agent (FEIBA; also called activated prothrombin complex concentrate) are approved by the US Food and Drug Administration for treatment of acquired hemophilia A.
The recommended dose range of rFVIIa for the treatment of patients with hemorrhage due to acquired hemophilia is 70 to 90 μg/kg repeated every 2 to 3 hours until hemostasis is achieved. The minimum effective dose in acquired hemophilia has not been determined.
Recommended doses of FEIBA depend on the type of bleeding.
— In joint hemorrhage, 50 U/kg is recommended at 12-hour intervals, which may be increased to doses of 100 U/kg. Treatment should be continued until clear signs of clinical improvement appear, such as relief of pain, reduction of swelling, or mobilization of the joint.
— For mucous membrane bleeding, 50 U/kg is recommended at 6-hour intervals under careful monitoring. If hemorrhage does not stop, the dose may be increased to 100 U/kg at 6-hour intervals.
— For severe soft-tissue bleeding, such as retroperitoneal bleeding, 100 U/kg at 12-hour intervals is recommended.
— Central nervous system bleeding has been effectively treated with doses of 100 U/kg at 6- to 12-hour intervals. One should not exceed a daily dose of FEIBA of 200 U/kg.
The response to bypassing agents is variable and does not correlate with the inhibitor titer. A major concern with the use of rFVIIa and activated coagulation factor concentrates is that there is no laboratory method available for predicting response to therapy or monitoring patients on therapy.
The major serious adverse event associated with bypassing agents is thrombosis. However, this risk is considered low when used for approved indications at the recommended doses.
A commercial plasma-derived porcine factor VIII concentrate was useful in the treatment of factor VIII inhibitor patients for approximately 20 years but was discontinued in 2004 because of viral contamination of the product. Porcine factor VIII has the advantage of potentially being guided by laboratory monitoring of recovery of factor VIII activity in plasma. However, the development of antiporcine factor VIII antibodies often precluded its long-term use.
Although acquired inhibitors may remit spontaneously, initiation of immunosuppressive therapy at the time of diagnosis to eradicate the inhibitor is recommended because of the serious course of this condition. A variety of immunosuppressive agents have been used, including cyclophosphamide, azathioprine, cyclosporine A, intravenous immunoglobulin, and rituximab. Plasmapheresis and immunoadsorption of the inhibitory antibody have been used. Finally, immune tolerance induction using human factor VIII has been used successfully.