Limited proteolysis of factor VIII. The major part of factor VIII circulates as a set of heterogenous dimers, consisting of a light (a3-A3-C1-C2) and heavy chain (A1-a1-A2-a2-B). The heavy chain is variably sized due to limited proteolysis within the B domain. Some of these cleavages may occur intracellularly at positions 1313 and 1648 (open downward arrows). Factor VIII can be converted into its active form by proteolysis in both the heavy and light chain by various serine proteases (closed downward arrows), including thrombin and factor Xa. Because proteolysis by factor Xa but not thrombin is inhibited by vWF, thrombin is probably the physiological activator of factor VIII. Proteolytic degradation of factor VIIIa proceeds through cleavages within the A1 and A2 domains by various serine proteases (upward arrows), and results in release of the a1 acidic region and bisecting of the A2 domain. In contrast to what has previously been assumed, cleavages within the light chain by factor IXa or factor Xa do not result in inactivation of factor VIII, but contribute to the development of factor VIII cofactor activity.