Inhibitors in hemophilia patients: current status and management

The development of inhibitor antibodies is a long-standing, well-documented complication of coagulation factor replacement therapy and is difficult to treat. Previous estimates of 5-15% of patients developing inhibitors may be low, since newer data suggest a wider range of occurrence. Factors that appear to affect inhibitor development include the severity of hemophilia, age, genetics, and, possibly, the type of replacement therapy administered. Recent studies raise the concern that recombinant factor therapies may be associated with more rapid development and higher levels of inhibitors in previously untreated patients. However, results of different studies are often difficult to compare owing to differences in methodology and populations studied. Further studies standardized in design and methods are clearly needed. Management of patients with inhibitors involves control of acute bleeding episodes and, over the long term, induction of immune tolerance for the coagulation replacement therapy. Many with low or moderate levels of inhibitors may be treated simply by administering higher doses of clotting factor. Other therapies appropriate for those with high levels of inhibitors include porcine F VIII and factor VIII "bypassing" agents, such as recombinant factor VIIa. Long-term immune tolerance has been achieved through the high-dose "Bonn" regimen and immunosuppressive regimens such as the "Malmö" method. Although management of inhibitor patients has improved, it still represents a major challenge. Further research is needed to identify which patients will develop inhibitors and tolerance, as well as to develop better methods to manage, reduce, or eliminate inhibitors from these patients.