Factor VIII (FVIII) in its activated form, FVIIIa, acts as a cofactor to the serine protease FIXa, in the conversion of the zymogen FX to the active enzyme (FXa). Missense mutations within the S577-Q584 region of FVIII have been associated with mild/moderate hemophilia A (HA) (Amano K et al. 1998; Celie PH et al. 1999; Jenkins PV et al. 2002). A functional assay demonstrated that the mutations S577F, V578A, D579A, and Q584R interfere with FVIIIa:FIXa-mediated stimulation of FX activation thus the effect of the mutations is to reduce the cofactor potential of FVIII in FXa generation. The Reactome event describes failed generation of FXa as the functional consequence of the FIXa interaction with HA-associated FVIIIa variants due to reduced ability of defective FVIII to act as a cofactor for FIXa within the intrinsic tenase complex.