Mechanisms regulating plasma levels of FVIII. (A) In the absence of VWF, plasma levels of FVIII are reduced because of proteolysis by activated protein C (APC) and accelerated receptor-mediated endocytosis. VWF D′D3 is able to stabilize plasma levels of FVIII presumably by regulating these clearance mechanisms. (B) VWF D′D3-Fc has a prolonged half-life relative to VWF D′D3 because of interactions with the Fc receptor FcRn recycling pathway. VWF D′D3-Fc is able to stabilize endogenous FVIII levels in VWF-deficient mice because of continual secretion of FVIII into the plasma. However, in hemophilia A mice, exogenous FVIII is not adequately protected from clearance and rapid degradation. Coinfusion of VWF D′D3-Fc and FVIII-Fc might result in recycling of both molecules through the FcRn endosomal pathway, leading to an extended half-life beyond that observed for FVIII-Fc alone.