FIGURE 2 | The key enzymatic and cellular events leading to clot formation.

The primary event initiating the coagulation pathway (a) occurs when activated factor VIIa (FVIIa) binds to tissue factor, which is present on extravascular tissue and activated endothelium (inflamed). This complex activates traces of FX and thrombin (FIIa). Thrombin, in turn, activates small amounts of cofactors FV and FVIII. The procoagulant signal is then rapidly amplified (b) via assembly of a series of enzymatic coagulation factor complexes^{88, 89} (see Fig. 3) that culminate in a burst of thrombin generation. Thrombin then directly propagates clot formation by cleaving fibrinogen to fibrin (the fibrous substance comprising the growing thrombus) and also activates FXIII, which stabilizes the clot by crosslinking fibrin fibres and several other proteins, including inhibitors of plasmin (c). Because the coagulation cascade results in an explosive release of thrombin, mechanisms exist (d) that attenuate and compensate thrombin generation through negative feedback. Attenuation occurs through inactivation of FVa by protein S (PS) and activated protein C (APC) generated by the thrombomodulin–thrombin complex. Excess thrombin is compensated by direct inhibition by antithrombin III (ATIII) via formation of the thrombin–anti-thrombin III (TAT) complex). Thrombin is highlighted in red to emphasize its many roles in coagulation. Platelets are activated very early in this process by exposed collagen and von Willebrand factor (vWF) or by thrombin. Their essential role is to form the primary haemostatic plug and also to provide an additional prothrombotic membrane surface for the coagulation process. The mature thrombus is thus composed of platelets bound by and embedded in a fibrin gel. Following haemostasis, the thrombus is resolved by the process of fibrinolysis (by, for example, tissue plasminogen activator (tPA) and plasminogen) as wound healing commences. FDP, fibrin degradation products; TM, thrombomodulin.

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