Biological considerations of plasma-derived and recombinant factor VIII immunogenicity

In hemophilia A, the most severe complication of factor VIII (FVIII) replacement therapy involves the formation of FVIII neutralizing antibodies, also known as inhibitors, in 25% to 30% of patients. This adverse event is associated with a significant increase in morbidity and economic burden, thus highlighting the need to identify methods to limit FVIII immunogenicity. Inhibitor development is regulated by a complex balance of genetic factors, such as FVIII genotype, and environmental variables, such as coexistent inflammation. One of the hypothesized risk factors of inhibitor development is the source of the FVIII concentrate, which could be either recombinant or plasma derived. Differential immunogenicity of these concentrates has been documented in several recent epidemiologic studies, thus generating significant debate within the hemophilia treatment community. To date, these discussions have been unable to reach a consensus regarding how these outcomes might be integrated into enhancing clinical care. Moreover, the biological mechanistic explanations for the observed differences are poorly understood. In this article, we complement the existing epidemiologic investigations with an overview of the range of possible biochemical and immunologic mechanisms that may contribute to the different immune outcomes observed with plasma-derived and recombinant FVIII products.