The evolving understanding of factor VIII binding sites and implications for the treatment of hemophilia A

Hemophilia A is caused by decreased or dysfunctional blood coagulation factor VIII (FVIII). Recent developments in the understanding of FVIII biology, in particular the nature of FVIII binding sites on platelets, may provide new insight into the limitations of current assays. Recent data suggest that the phospholipid vesicles, which represent nonphysiologic membranes of high phosphatidylserine (PS) content, poorly reflect functional FVIII binding sites critical to coagulation. This narrative review describes the function of FVIII in clotting and discusses our evolving understanding of FVIII binding sites and their clinical implications. Refined models of FVIII binding sites have the potential to improve FVIII assays, possibly improving bleeding risk stratification for patients with mild and moderate hemophilia A. They may also support earlier and more accurate detection of inhibitors, before they are clinically evident.