Refractory hemophilia

Physiology - Hematologic

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.

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.

Sources

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    Thromb Haemost;1997 Jun;77(6):1113-9

    [PubMed: 9241742]

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