To clear or to fear: An innate perspective on factor VIII immunity

•FVIII inhibitor development involves a combination of innate immune modulators.•Clearance and immunity is influenced at 3 levels: the protein, cell, and location.•Cells associated with FVIII half-life may influence the immune response against FVIII. The enigma that is factor VIII immunogenicity remains ever pertinent in the treatment of hemophilia A. Development of neutralizing antibodies against the therapeutic protein in 25–30% of patients likely depends on the appropriate activation of the innate immune response shortly following antigen encounter. Our understanding of this important immunological synapse remains ill-defined. In this review, we examine the three distinct factors contributing to the fate of factor VIII almost immediately after infusion: the characteristics of the protein, the cell, and the microenvironment. We propose a continuum between clearance and antigen presentation that facilitates removal of FVIII from circulation leading to either tolerance or immunity.