Epidemiology of inhibitors and current treatment strategies.

The development of inhibitors is currently one of the most serious complications in the treatment of hemophilic children. Prospective studies of previously untreated patients (PUP) showed that up to 52% of patients with severe hemophilia A developed inhibitors during the first 50 exposure days (ED) (>100 for outliers). Inhibitor development is influenced by the type of hemophilia, the severity and the type of mutation. No significant differences in inhibitor incidence were found in prospective studies conducted with plasma-derived or recombinant products. However, no comparative study has been finished yet. A still ongoing prospective, multi-center PUP-study initiated by the German, Austrian and the Swiss Society of Thrombosis and Hemostasis Research (GTH) foresees the direct comparison of different types of concentrates with regard to inhibitor development. Preliminary results (update February 2002) show a slightly higher inhibitor development (p=0.08) in severely affected hemophilia A patients treated with recombinant factor (F) VIII concentrates. However, the groups are very small and statistically reliable statements cannot be made at the moment. In case of inhibitor development rapid inhibitor elimination and immune tolerance induction (ITI) is the preferred way to reduce the high risk of bleeding episodes. In this respect, various therapeutic regimens, such as the administration of high doses of FVIII twice daily (Bonn protocol), or lower doses three times weekly (van Creveld protocol), have been attempted. Elimination of inhibitors from plasma by immune adsorption followed by immune suppression (Malmö protocol) has also been used. The influence of the type of concentrate used for ITI has never been investigated comparatively. A longitudinal study of ITI at our center showed a significantly decreased success rate since the introduction of high purity plasma derived and recombinant FVIII products using the Bonn protocol. In inhibitor patients who showed an unsatisfactory response to treatment with FVIII concentrates with very little or no VWF the change to concentrates containing high amounts of von Willebrand factor (VWF) increased success rates up to 90%. These observations raise the question of whether VWF plays an important role in the induction of immune tolerance.