Thrombin generation is initiated when the protease factor VIIa and the cofactor tissue factor form a complex that converts factor X to factor Xa. Factor Xa, with its cofactor factor Va, catalyzes conversion of prothrombin to thrombin. Factor VIIa/tissue factor also converts factor IX to the protease factor IXa (reaction 1), which, in the presence of factor VIIIa, activates additional factor X to sustain thrombin generation. Factor IX is also converted to factor IXa by factor XIa (reaction 2). In the original cascade/waterfall models of coagulation, factor XI was activated by the enzyme factor XIIa during a process called contact activation. However, the absence of abnormal bleeding in factor XII deficient individuals indicates that other mechanisms exist for factor XI activation. In the figure, factor XI is activated by thrombin generated initially through the factor VIIa/tissue factor complex, creating a feedback loop (gray arrows) for factor IX activation. Coagulation protease precursors are indicated by black type, and the active forms of the proteases are shown within blue half-ovals. Cofactors are shown within pink half-ovals. F, factor.