Models of thrombin generation. For all panels, plasma proteases are indicated in black lettering, with the activated forms indicated by a lower case “a.” Cofactors are indicated in red ovals. (A) Thrombin generation. Major protease activation reactions during thrombin generation are indicated by black arrows. Thrombin generation at a wound is typically initiated by a complex formed between the plasma protease factor VIIa and the cofactor TF. (B) The kallikrein-kinin system (KKS). On a surface (represented by the gray rectangle), factor XII (FXII), and PK undergo reciprocal activation to FXIIa and PKa. PKa cleaves HK, releasing BK. (C) The cascade-waterfall model of thrombin generation. In this model, the process is initiated by activation of FXII through the reactions shown in panel B. FXIIa then converts FXI to FXIa, which then activates FIX. The series of reactions indicated by the yellow arrows is referred to as the intrinsic pathway. Image adapted from Gailani and Gruber.¹²  BK, bradykinin; TF, tissue factor.