An alternative schematic of secondary hemostasis: Thrombin generation is initiated by the extrinsic tenase, which consists of a complex of tissue factor (the cofactor), factor VII (FVII, the enzyme), calcium (required for FVII binding to membrane surfaces) and surface phospholipids on extravascular fibroblasts. Once bound to tissue factor, FVIIa forms a self-activating complex and cleaves factor X (FX) to its activated form (FXa), which is also bound to the membrane surface, in a calcium-dependent manner. The FXa then cleaves prothrombin (factor II) to thrombin. The extrinsic tenase, with FXa, is rapidly inhibited by tissue factor pathway inhibitor, generating a small amount of thrombin, which is insufficient, by itself, to form fibrin from fibrinogen. But that small amount of thrombin amplifies its own production on the surface of propagating platelets, by activating factor XI (FXI) of the intrinsic pathway. Thrombin also activates the cofactors of the intrinsic and common pathways, factors VIII (FVIII) and V (FV), respectively, vastly increased their associated enzyme activities. Activated FXI converts factor IX (FIX) to its active form. When bound to phosphatidylserine (PS) on the platelet surface (with the aid of calcium), FIX with its cofactor FVIIIa activates FX on the platelet surface (FIXa, FVIIIa, calcium and PS are also called the intrinsic tenase complex). The platelet bound FXa, in the presence of its cofactor, FVa, calcium and PS, then generates a large amount of thrombin, called the thrombin burst. Release of FV from stores in platelets boosts local concentrations, facilitating amplification of thrombin generation. Note that thrombin is a potent platelet activator, facilitating membrane flipping and PS exposure on the outer membrane leaflet and degranulation with release of other agonists and coagulation factors, such as FV and fibrinogen. Once large amounts of thrombin are generated in the thrombin burst, thrombin then cleaves fibrinogen to soluble fibrin, activates factor XIII (FXIII) to FXIIIa, which then crosslinks the soluble fibrin, forming stable crosslinked fibrin. At the same time, the thrombin activates carboxypeptidase B, also called thrombin-activatable fibrinolysis inhibitor or TAFI, which prevents breakdown of the clot as it is being formed. Although not depicted here, prothrombin is also bound to the PS surface via calcium.
The tissue factor-FVIIa complex can also activate FIX to FIXa on the fibroblast surface, via the alternate pathway. The FIX can diffuse from the fibroblast to the platelet surface, thus increasing the amount of FIXa for the intrinsic tenase complex. Unlike FIXa, FX cannot readily dissociate from the membrane surface and is rapidly inhibited by plasma inhibitors if it does, so the FXa formed on the fibroblast surface stays there, necessitating FXa generation by the intrinsic tenase on platelets.
