INSIGHT in risk factors and treatment of inhibitors in nonsevere hemophilia A

Hemophilia A is an inherited X-linked bleeding disorder that occurs in male offspring of carrier females. In these individuals a mutation in the F8 gene, located on the X-chromosome, causes a deficiency of the factor VIII protein, clotting factor VIII.
The worldwide prevalence of hemophilia is 1 in 5000 live male births, with one-third of the patients affected by severe hemophilia A and two-thirds of the patients have nonsevere disease.
In patients with hemophilia A there is an impaired hemostasis due to a reduction of their factor VIII plasma level. This is associated with clinical symptoms of spontaneous bleeds in joints and muscles.
An extremely severe and challenging complication of treatment with factor VIII concentrates in hemophilia A patients is the development of anti-factor VIII antibodies that inhibit (neutralize) the factor VIII activity, also referred to as inhibitors. This complication occurs in 25-30% of the severe hemophilia patients. Inhibitors seem to occur less frequently in nonsevere hemophilia A patients, although studies on inhibitor incidence in this group of patients are scarce.
When a nonsevere hemophilia A patient develops an inhibitor, the phenotype of the disease may change dramatically. Nonsevere haemophilia A patients would normally only experience incidental bleeding episodes, but after inhibitor development the bleeding phenotype may aggravate dramatically, especially if the inhibitor reduces the endogenous factor VIII plasma levels. This is associated with an increased morbidity and mortality.
This thesis focuses on the risk factors and treatment of inhibitors in nonsevere hemophilia A.