FIGURE 3 | Enzymatic relationships within the coagulation pathway.

Recombinant coagulation factors currently in clinical use or in development are surrounded in yellow. Thrombin (FIIa) is highlighted in red to emphasize its central role. Under normal physiologic conditions, the primary initiating event (upper right bold heading) occurs when circulating activated factor VII (FVII (FVIIa)) binds to exposed tissue factor and small amounts of FIXa and FXa begin to be generated⁹⁰. FXa provides positive feedback by catalysing the formation of more FVIIa and also generates small amounts of thrombin, which begins activating the cofactors V and VIII⁹¹. These initial catalytic events therefore provide the elements for the formation of three essential procoagulant complexes, which sequentially amplify the procoagulant stimulus in a positive feed-forward loop. These complexes are the FXa–FVIIa–tissue factor complex ('nine-ase'), which activates FIX⁹²; the FIXa–FVIIIa complex ('tenase'), which activates FX; and the FXa–FVa complex (PROTHROMBINASE), which then produces a burst of thrombin that directly propagates clot formation^{92, 93}. These complexes are functionally analogous and structurally homologous and all require an exposed anionic phospholipid (PL) surface (for example, activated platelets (Plt)) and Ca²⁺ for assembly and catalysis⁹⁶. Deficiencies of any of the protein elements comprising these complexes can result in a severe bleeding disorder. Contact activation of coagulation is also depicted, but is of doubtful significance under normal physiological conditions^{94, 95, 96, 97}. HK, high-molecular-mass kininogen.

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