Figure 1. Contact Activation and Thrombin Generation.

(A) Contact Activation. Proteolytic reactions involved in contact activation are shown on a hypothetical surface represented in gray. Factor (F) XII binding to the surface facilitates autocatalytic conversion of FXII to FXIIa. FXIIa converts prekallikrein (PK) to α-kallikrein, which activates additional FXII and cleaves high-molecular-weight kininogen (HK, yellow arrows), liberating bradykinin (BK). HK also serves as a cofactor in this process by facilitation PK binding to the surface. FXIIa also activates FXI to the protease FXIa. (B) The Classical Coagulation Cascade. FXIa generated in the process described in Panel A triggers plasma coagulation by converting FIX to FIXa. FIXa in turn activates FX to FXa, which then converts prothrombin (F11) to thrombin (F11a). (C) A Current Model of Thrombin Generation Showing Its Relationship to Contact Activation. Reactions within the pink box are the major proteolytic steps involved in thrombin generation at a site of injury. The FVIIa/tissue factor (TF) complex initiates thrombin generation by activating FX and FIX. FXa converts prothrombin (F11) to thrombin (F11a) in the presence of the cofactor FVa, while FIXa sustains FX activation in a FVIIa-dependent manner. In this model, FXI can be activated by thrombin (blue arrow) to FXIa, which sustains coagulation by activating additional FIX. FXI can also be activated by FXIIa, serving as a bridge between contact activation and thrombin generation. There is some evidence that FXIa can also convert FXII to FXIIa (gray arrow). In panels B and C, cofactors are shown in blue ovals. Calcium (Ca²⁺) and phospholipid (PL) dependent reactions are indicated. For all panels, red arrows indicate the reciprocal activation of FXII and PK, and green arrows the activation of FXI by FXIIa.