Factor VIII, a non-covalent heterodimer comprised of a heavy chain (A1-A2-B domains) and light chain (A3-C1-C2 domains), circulates as an inactive procofactor in complex with von Willebrand factor. Metal ions are critical to the integrity of factor VIII, with Cu and Ca ions stabilizing the heterodimer and generating the active conformation, respectively. Activation of factor VIII catalyzed by thrombin appears dependent upon interactions with both anion-binding exosites I and II, and converts the heterodimer to the active cofactor, factor VIIIa. This protein, comprised of A1, A2, and A3-C1-C2 subunits, is labile due to weak affinity of the A2 subunit. Association of factor VIIIa with factor IXa to form the intrinsic factor Xase complex is membrane-dependent and involves multiple inter-protein contacts that remain poorly characterized. This complex catalyzes the conversion of factor X to factor Xa, a reaction that is essential for the propagation phase of coagulation. The role of factor VIIIa in this complex is to increase the catalytic efficiency for factor Xa generation by several orders of magnitude. Mechanisms for the down-regulation of factor Xase focus upon inactivation of the cofactor and include dissociation of the A2 subunit as well as activated protein C-catalyzed proteolysis.