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. This evidence concerns the gene F8 and von Willebrand disease 3.