FVIII 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. FVIII circulates in complex with VWF. Binding to VWF is approximated by its dimeric D′D3 fragment as illustrated, with major contacts between D′ and the C1 domain. Additional interactions occur with the A3 domain 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 FVIIIa from VWF. FVIIIa is then available to interact with membranes and FIXa to form the extrinsic Xase complex of coagulation.