Tolerance to Factor VIII in the Era of Non-Factor Therapies: Immunological Perspectives and a Systematic Review of the Literature.

Persons with hemophilia A (PWHA) lack clotting factor VIII (FVIII) due to a genetic mutation in the F8 gene. The administration of FVIII concentrate leads to the development of neutralizing anti-FVIII antibodies (inhibitors) in about 30% of children with severe hemophilia A. The other 70% of children do not mount a detectable antibody response, suggesting that they may have developed tolerance towards FVIII. Our knowledge on the underlying immunological mechanisms that determine formation of inhibitors or apparent tolerance to FVIII is limited. Up to recently, FVIII concentrates were regularly used as prophylaxis. In the last years, Non-Factor Therapy (NFT) for prophylaxis is increasingly used, in which case FVIII concentrate administration is limited to treatment for bleeding or perioperative hemostasis. As NFT is very effective in the prevention of bleeds, patients may not be exposed to the deficient FVIII protein for periods up to a year or longer. Thus, while in the past persons with severe hemophilia were frequently exposed to the deficient antigen, exposure is now reduced to incidental treatment moments. It is currently not known how this will affect the tolerance for FVIII. In this review, we will discuss tolerance to FVIII from a clinical, immunological and epidemiological perspective. We aim to provide an outlook on the effect of reduced FVIII exposure on tolerance for FVIII in PWHA.