Mild/moderate haemophilia A: new insights into molecular mechanisms and inhibitor development.

In mild/moderate haemophilia A (MHA) patients, many factor VIII (FVIII) gene defects, mainly missense mutations, have been identified and greatly improved the understanding of the structure and function of FVIII molecule. Characterization of the molecular mechanisms involved in MHA has helped to identify regions critical for proper FVIII biosynthesis, thrombin activation, intramolecular stability as well as binding regions for important intermolecular interactions with von Willebrand factor, factor IXa and the phospholipid surface. Some missense mutations were also recognized as contributing factors to inhibitor development in MHA, in parallel to acquired factors such as inflammatory state or intensity of treatment. Treatment of MHA with inhibitor patients raises questions on how best to stop or prevent bleeding episodes and eradicate the inhibitor. Longitudinal data collection is currently being conducted in France and Belgium to enhance our knowledge in this field and to further help make treatment decision. The description of mutations in MHA finally contributed to the identification of epitopes involved in the immune response to FVIII. In some patients, the epitope specificity of inhibitor antibodies recognizing normal exogenous FVIII alone and not patient ('self') FVIII was described. This distinguished epitope specificity could also be demonstrated at the T-cell clonal level. One might expect that these molecular studies will have a major impact on development of new FVIII products in the future.