Models of thrombin generation. Shown are major enzymatic reactions (represented by arrows) during plasma coagulation. In each reaction a plasma zymogen (black Roman numerals) is converted to an active protease (Roman numerals followed by “a”). Coagulation cofactors are shown as red ovals. Requirements for calcium ions (Ca2+) or phospholipids (PLs) for specific reactions are indicated within circles. Green arrows indicate reactions involving factor XI (XI) or factor XIa (XIa). (A) Tissue factor (TF)-initiated thrombin generation. Coagulation is initiated when FVIIa binds to TF that is exposed to blood at a wound site (gray circle). The FVIIa-TF complex converts FX to FXa leading to initial thrombin generation. FVIIa-TF also converts FIX to FIXa, which sustains thrombin generation by activating additional FX. In this scheme FXIa serves a limited role, generating some FIXa. FXI may be activated by thrombin or other unknown proteases (?) in this system. Its activation is not dependent on FXII. (B) Contact activation–initiated thrombin generation. The process is initiated by exposure of plasma to a surface (typically carrying a negative charge), which triggers FXII activation by a process called contact activation. This sets off a series (cascade) of enzymatic reactions culminating in conversion of prothrombin to thrombin. Here, FXI is a component of the contact activation process that triggers coagulation and is a major contributor to thrombin generation.
