Coagulation

In a normal blood vessel, cells expressing tissue factor are physically separated from components of the blood coagulation network, thus preventing initiation of coagulation. In addition, coagulation inhibitors and inhibitors of platelet aggregation are present on the endothelial surface and maintain vessel patency [18].

If a vessel is damaged, there is a localised haemostatic response with initiation of coagulation initiated by tissue factor exposure. Coagulation happens with the exposure of the circulating clotting factor, factor VII (FVII), to membrane-bound tissue factor. Activation of FVII to FVIIa (shown in red in the figure) and the formation of a complex of tissue factor-FVIIa results in the activation of FIX and FX by the complex [18].

In the absence of its activated cofactor FVa, FXa generates only trace amounts of FIIa (thrombin) from prothrombin (FII) (figure part A). The thrombin generated is not enough to initiate significant fibrin polymerisation, but thrombin in this initiation stage of coagulation is capable of activating FV, FVIII and FXI. In this amplification phase of coagulation, FXIa activates FIXa which forms a complex with FVIIIa. This is the ‘tenase complex’ (FVIIIa–FIXa) (shown in blue in figure part B) that activates sufficient FXa to form a complex with FVa, the ‘prothrombinase complex’ (FVa–FXa) (shown in orange in figure part B). This results in the explosive generation of thrombin that ultimately leads to generation of a fibrin clot [18].



Initiation and amplification pathways in coagulation
A – Initiation B – Amplification

Platelets then play a key role, with platelet activation/aggregation initiated by the exposure of extravascular collagen and binding of von Willebrand factor (vWF). vWF is a key protein for platelet binding and activation as it contains binding sites for collagen, fibrinogen and the platelet receptor, glycoprotein Ib [18].


Figure: intravascular tissue factor exposure results in the initiation of coagulation, which leads to pathological thrombosis, shown here as a thrombus, a thrombosis that is occluding a vessel, and the embolisation of a thrombus.