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Factor VIII (FVIII) and von Willebrand factor (vWF) are glycoproteins that circulate in plasma in a tightly bound complex. Structural defects or deficiencies in either glycoprotein are responsible for the development of the most common inherited bleeding disorders: hemophilia A and von Willebrand disease (vWD). These diseases manifest spontaneous bleeding in the severe form of the disease. Based on circulating levels of plasmatic and, in vWD, platelet levels, bleeding manifestations may occur only when challenged with trauma or surgery, and thus may go undetected. The immunogenicity of replacement products for both of these diseases can lead to antibody formation. In hemophilia, inhibitors can occur early—with mean exposure days as low as nine—and continue throughout life, and have been reported as high as 52%. Severity of disease, ethnicity, setting, and type of product are factors affecting outcome. Inhibitors following treatment of vWD are rare. The challenge of inhibitor induction in hemophilia is both the therapy for bleeding episodes and their eradication. Factor-bypassing products (FBPs) have been used to treat bleeding episodes in patients with inhibitors. However, these products are less effective than FVIII concentrates as hemostasis cannot be predicted, and they are also expensive. Patients treated on demand with FBPs also have a higher morbidity rate, with more likely chronic synovitis, and have an early onset of degenerative arthritis and long-term joint arthropathy, in addition to having bleeding episodes. Immune tolerance induction (ITI) therapy is an alternative approach that aims to create tolerance to inhibitors and return patients to their original state.
The development of inhibitors in patients with hemophilia A has been noted in 48% of patients with a family history of inhibitors, in comparison with 15% of cases with no family history of inhibitors.1 In an analysis of 249 families with hemophilia A, a concordance of 78.3% was calculated between siblings for the presence of inhibitors.2 Inhibitor incidence in severe hemophilia A is twice that in African patients compared with Caucasian patients.3,4 These propensities are believed to be influenced by both the FVIII genotype and the genetic characteristics of the immune system.