Cleavage of factor VIII (FVIII) light chain promotes a change in the conformation of the C2 domain that facilitates dissociation from von Willebrand factor (VWF) and enhances the affinity of FVIIIa for anionic phospholipid surfaces (Saenko et al. 1998). Factors VIIIa associates with anionic phospholipid via a multistep process in which rapid association is followed by a slower step yielding higher affinity binding (Gilbert GE et al. 1990; Bardelle C et al. 1993). Crystallographic studies of the C2 domain of FVIII and two‐dimensional crystallography of FVIII bound to phospholipids identified multiple surface-exposed residues with hydrophobic and basic side chains that contribute to the electrostatic interaction with acidic phospholipid headgroups (Pratt KP et al. 1999; Stoilova‐McPhie S et al. 2002; Liu Z et al. 2010). Site‐directed mutatgenesis of residues believed to mediate FVIII binding to phospholipids confirmed the structural analysis findings (Gilbert GE et al. 2002, 2012). In addition, a membrane-binding motif on the FVIII C1 domain contributes to membrane binding and cofactor activity (Hsu TC et al. 2008; Meems H et al. 2009; Lü J et al. 2011). Further, high resolution crystal structures of the FVIII C2 domain also allowed modeling of hemophilic missense mutations in both the C1 and the C2 domains, which can indicate residues that are important for function or stability of the protein. (Liu ML et al. 2000; Spiegel PC et al. 2004). A change in the size or dimension of a single side chain may reduce the affinity of the interaction but is unlikely to completely prevent membrane binding (Liu ML 2000). Thus, a relatively small percentage of hemophilia A (HEMA)-associated mutations in the F8 gene has been reported to affect the membrane binding (Liu ML et al. 2000; Spiegel PC et al. 2004; Du J, et al. 2015). The Reactome event describes the defective interaction between the thrombin-activated FVIIIa protein and phospholipid membrane surfaces caused by HEMA-associated FVIII variants, such as A2220P, A2220del and Q2330P.