Models of thrombin generation. (A) Contact activation-initiated thrombin generation. In the cascade/waterfall hypothesis of coagulation, thrombin generation is initiated by the process contact activation (gray oval). Contact activation involves reciprocal activation of the protease precursors fXII and PK on a surface (typically a negatively charged surface). HK serves as a cofactor for the reaction by facilitating PK binding to the surface. FXIIa then activates fXI, in a reaction that also requires HK, setting off the series of calcium-dependent proteolytic reactions that culminates in thrombin generation. (B) TF-initiated thrombin generation. In this more current scheme, thrombin generation is initiated by factor VIIa in plasma binding to TF, a membrane protein expressed on the surface of cells beneath the blood vessel endothelium. The factor VIIa/TF complex activates factor X to factor Xa and factor IX to factor IXa. Factor Xa converts prothrombin to thrombin in the presence of factor Va and factor IXa sustains the process by activating additional factor X in the presence of factor VIIIa. The reactions indicated by the black arrows form the core of the thrombin-generation mechanism in vertebrate animals. Mammals have fXIa, which provides another mechanism for fIX activation (red arrow). Although fXI is activated by fXIIa during contact activation, this reaction is not shown in this scheme because it does not appear to be required for hemostasis. FXI can be activated by thrombin generated early in the coagulation process (gray arrows), explaining the lack of a bleeding disorder in people lacking fXII. In (A) and (B), the precursors (zymogens) of trypsin-like enzymes are indicated in black lettering, with active forms indicated by a lowercase “a.” Protein cofactors are indicated by Roman numerals in yellow ovals.