Factor VIII interactions with von Willebrand factor (VWF) during factor VIII activation

Factor VIII is a heterodimer with a domain structure of A1-A2-B and A3-C1-C2. In the standard view and in accordance with crystal structures, they are illustrated with the polypeptide chain running clockwise from A1 to C2. Factor VIII circulates in complex with von Willebrand factor (VWF). Binding to VWF is approximated by its dimeric D'D3 fragment as illustrated, with major contacts between D' of VWF and the C1 domain of factor VIII. Additional interactions occur with the A3 domain of factor VIII and the a3 acidic peptide as well as the C2 domain. Thrombin cleavage of FVIII liberates the a3 peptide and the B domain, resulting in the dissociation of the resultant factor VIIIa from VWF. Factor VIIIa is then available to interact with membranes and activated factor IX (FIXa) to form the intrinsic X-ase complex of coagulation.