The inhibitors (autoantibodies) are usually polyclonal IgG with specificity against various epitopes on factor VIII. The binding of autoantibodies partially or completely neutralizes the action of factor VIII molecules. Antibodies in hemophiliacs have broad specificity while the autoantibodies in non-hemopheliacs has narrower specificity (ie, against fewer epitopes on Factor VIII) (4). Asymptomatic healthy blood donors may have a low titer factor VIII inhibitor (<2 Bethesda Unite or lower) (1). Such inhibitors are kept in check at least in part by the production of corresponding anti-idiotypic antibodies. Normal homeostasis of this network of interacting molecules, idiotypies and anti-idiotypes is disrupted by the overproduction of inhibitors; the development of hemophilia follows (3, 5).
II. Laboratory Diagnosis:
Confirmation of the factor VIII inhibitor is achieved by the employment of the Bethesda assay. This assay, which was standardized by a group of hematologists meeting in Bethesda, Maryland in the mid-1970's, is based on the ability of the patient's plasma containing the factor VIII inhibitor to inactivate factor VIII present in normal pooled plasma. Dilutions of the patient's plasma are incubated with normal pooled plasma for 2 hours at 370C, and then the residual factor VIII is measured. One Bethesda unit (BU) is defined as the quantity of inhibitor that neutralizes 50% of the factor VIII in normal plasma in 2 hours at 370C. For consistency, the least dilution of patient's plasma that inactivates exactly or almost exactly half the factor VIII in the incubation mixture is used in the calculation of Bethesda unit (6). The Bethesda method assumes a linear relationship between the patient's plasma dilution and residual factor VIII activity, and thus is best suited for measuring the amount of inhibitor in hemophiliacs. However, spontaneous (acquired) factor VIII inhibitors in non-hemophiliacs often demonstrate a complex, non-linear relationship and the Bethesda assay may underestimate the potency of the inhibitor. (6, 8). Unfortunately, there is no strict correlation between the titer levels and severity of disease (1).
NovoSeven was approved by FDA in 1999 for the treatment of bleeding in patients with hemophilia A and B inhibitors (alloantibodies), acquired inhibitors (autoantibodies) to factor VIII, and congenital factor VII deficiency. The site of action of NovoSeven is through the extrinsic pathway, therefore bypassing the intrinsic pathway (factors VIII and IX). Approximately 70% of patients with acquired inhibitors to Factor VIII or IX and acute bleeding will respond to NovoSeven. NovoSeven has been shown to be safe to use. There has been no evidence of allergic reaction, thrombosis, thrombocytopenia, or disseminated intravascular coagulation. A drawback of NovoSeven is that it requires frequent dosing due to its short half-life (2-3 hours) (4, 10).
The ultimate therapeutic goal is eradication of the inhibitor (autoantibodies), therefore the cure of the disease. Immunosuppresive regimen with corticosteroids, cyclosporine, and cyclophosphamide, alone or in combination, lead to remission in 50-70% cases (11). Intravenous immunoglobulin may decrease the circulating autoantibody level by modulating the immune system through idiotype/anti-idiotype interaction (1, 5). In summary, management of patients with inhibitors to factor VIII requires the combined approaches of achieving hemostasis and immunosuppressive (immumodulating) therapy to eradicate the inhibitor.
Contributed by Lirong Qu, MD, Ph.D, Kathy Puca, MD, Joseph Kiss, MD and Darrel Triulzi, MD