The etiology of inhibitor development in children with severe hemophilia A

Patients with severe hemophilia, a deficiency of functional clotting factor VIII, typically suffer from joint and muscle bleedings spontaneously or after minor trauma. The bleeding tendency can be effectively corrected by intravenous substitution of factor VIII products. However, about 25% of patients with severe hemophilia A develop inhibitors, anti-factor VIII antibodies, that neutralize infused clotting factor. More knowledge on the genetic and environmental determinants of the risk of inhibitor development may contribute to the prediction of patients’ individual risks of developing inhibitors. Therefore, in this thesis we aimed to identify patient-related and environmental risk factors of inhibitor development in patients with severe hemophilia A. In a single center cohort study we found that the type and location of the F8 gene mutation were important determinants of inhibitor development. In a systematic review and a meta-analysis we pooled data from 30 studies on a total of 5383 patients, including 1029 inhibitor patients to provide more precise estimates of the relative risks of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. That not only genetic risk factors but also non-genetic risk factors play a role in the development of inhibitors, is illustrated by a report of a discordant anti-factor VIII antibody response in a pair of monozygotic twin brothers. Therefore we further focused on non-genetic risk factors in an international multi-center cohort study among severe hemophilia A patients born between 1990 and 2000 (the CANAL Study). In this study we found that intensive treatment with factor VIII, such as during surgery or major bleeds, was an independent risk factor for inhibitor development. The previously reported association between an early age at first exposure and the risk of inhibitor development was largely explained by early, intensive treatment. Furthermore, early regular prophylaxis appeared to protect patients with hemophilia against the development of inhibitors. Contrary to several earlier reports, plasma-derived factor VIII products with considerable concentrations of VWF did not confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products. Furthermore, switching between factor VIII product brands did not increase the inhibitor risk. To examine the association of dose, frequency and the time of starting factor VIII prophylaxis with the incidence of inhibitors we set up a large, international cohort study including 606 patients with severe hemophilia A born between 2000 and 2010. The findings suggested that prophylaxis does not affect the development of early inhibitors. It may, however, prevent late inhibitors, especially in patients with low risk F8 mutations. All doses and frequencies of prophylaxis used in our cohort carried similar inhibitor risks. After studying 20 years of hemophilia treatment still many questions remain open. More knowledge about the risk factors of inhibitor development is needed, for it is a condition for prediction and possibly even prevention of the development of inhibitors in patients with severe hemophilia A. If we are able to prevent inhibitor development, the morbidity of patients with hemophilia will be greatly improved. Moreover, inhibitors will then not hinder the cure of hemophilia by gene therapy.