Refractory hemophilia

Typically, hemophilia A and B are treated with replacement of the missing factor (ie, factor VIII or factor IX concentrates). However, patients can develop factor inhibitors, which are IgG antibodies directed against the deficient factor. This usually occurs soon after replacement therapy has been started and is more common in patients with hemophilia A than in those with hemophilia B. As many as 25-40% of patients with severe hemophilia A are reported to have factor VIII inhibitors. It is often not possible to neutralize high titer inhibitors even with administration of very high levels of replacement therapy. Inhibitors are suspected when an increase in the frequency of bleeding occurs. This may be seen when a mild or moderately deficient patient is converted to a more severe state due to inhibitor development. Diagnosis is made by measuring the factor VIII inhibitor activity by the Bethesda assay, which both establishes the diagnosis of factor VIII inhibitor and quantifies the antibody titer.

Treatment of factor inhibitors include the use of agents other than factor VIII (bypass products) and/or inhibitor ablation via immune tolerance induction. In patients with usual bleeding who have high titers of inhibitors, bypass products are generally used. These include prothrombin complex concentrates and recombinant human factor VIIa. Prothrombin complex concentrates and activated prothrombin complex concentrates contain proteases that account for their procoagulant activity. They are partially purified mixtures of the vitamin K-dependent clotting factors prepared from plasma. The proteases are short-lived, therefore, initial hemostasis may be followed by breakthrough bleeding between doses. In addition, there is a risk of thrombosis, the most common of which is myocardial infarction. Prothrombin complex concentrates and activated prothrombin complex concentrates are expensive, carry a risk of significant complications, and provide unpredictable hemostasis.

Another bypass product used for “refractory” patients is factor VIIa. It is effective in as many as 90% of patients. There are many theories about how factor VIIa works in this setting, one of which involves binding to the platelet surface and restoring platelet surface- factor X activation. This interaction is deficient in hemophiliacs due to the absence of factor VIII/IX complexes. There is a smaller risk of systemic activation of coagulation, compared to prothrombin complex concentrates and activated prothrombin complex concentrates. If factor VIIa activity is localized to the platelet surface, it would be subject to normal control mechanisms of coagulation which may explain the lower rate of systemic thrombotic complications. Studies have shown no statistical difference in efficacy between factor VIIa and prothrombin complex concentrates.

Immune tolerance induction involves exposure to repetitive doses of factor VIII. Usually this illicits an initial rise in antibody titers, followed by a progressive reduction to low or undetectable titers. Immune tolerance usually needs to be maintained by continued exposure to factor VIII. Immune tolerance induction may also be used in patients with factor IX deficiency, however, it may be associated with nephrotic syndrome.