An update on the ‘danger theory’ in inhibitor development in hemophilia A

ABSTRACTIntroduction: Nowadays, one of the most serious treatment complications in hemophilia A is the formation of neutralizing antibodies against coagulation factor VIII (FVIII). These so-called inhibitors develop in about 30% of all patients with severe hemophilia A. Once formed, inhibitors reduce FVIII efficacy in blood coagulation, which has a negative impact on patients’ health and quality of life and significantly increases hemophilia A treatment costs. The pathophysiology of inhibitor development is a complex and multi-causal process, in which both genetic factors as well as environmental factors participate. So-called ‘danger signals’ are considered contributors to inhibitor formation, and can be triggered by surgery, joint bleeds or infections. A pro-inflammatory tissue micro-environment is thereby established, which is characterized by the upregulation of costimulatory molecules on antigen-presenting cells (APCs), that can facilitate the alloimmunization to FVIII and thereby inhibitor formation...