Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors.

The appearance of polyclonal antibodies inhibiting the function of exogenous factors VIII (FVIII) and IX (FIX) continues to be a major challenge in the treatment of patients with congenital haemophilia. Why these inhibitors develop in 10-20% of patients with haemophilia A, and in 1-5% of patients with haemophilia B, remains largely unexplained. The antibodies, however, are characterized by several features that may have implications for the immune process by which they occur. The FVIII antibodies are mainly directed towards the A2, A3 and C2 domains, thereby interfering with the function of the factor Xase complex, the binding of FVIII to von Willebrand factor, and the binding of FVIII to phospholipid membranes. The FIX epitopes are localized to the NH(2)-terminal gamma-carboxyglutamic acid region and the serine protease domain. Genetic risk factors are known to be of importance in the development of inhibitors, whereas the impact of non-genetic factors is less clear. However, based on studies of related subjects, it is obvious that non-genetic factors are of importance as well. Putative factors currently debated include age at the start of treatment, treatment in association with immune challenges, the type of product, and the mode of administration. Most of the findings reported to date, however, derive from small cohorts that have not been sufficiently well characterized with respect to genetic risk profile. Therefore, additional studies are required to quantify the impact of non-genetic factors on the pathophysiologic process of inhibitor development.