F8 and von Willebrand disease (hereditary or acquired): The physiological relevance of VWF/FVIII complex formation is exemplified by the markedly reduced FVIII plasma levels in patients with undetectable VWF levels (VWD-type 3) or with a defect in the FVIII-interactive site of VWF (VWD-type 2N).51–53 Indeed, the majority of VWD-type 2N mutations are located in the region spanning residues 764–1035,54 suggesting that these mutations affect FVIII binding directly by modulation of the FVIII interactive site.