Back to basics: the coagulation pathway.

The classic coagulation cascade model of intrinsic and extrinsic coagulation pathways, i.e. contact activation pathway and tissue factor pathway, has been widely modified. The cascade can be categorized as follows: 1) initiation by tissue factor (TF), 2) amplification by the intrinsic tenase complex, and 3) propagation on activated platelets. TF-FVIIa forms an extrinsic tenase complex and activates FX to FXa and FIX to FIXa. FXa-FVa forms a prothrombinase complex that converts prothrombin into thrombin. At this initial stage of coagulation, only small amounts of thrombin are generated owing to the low circulating levels of FVa. The generated thrombin, although in minor quantities, is sufficient to prime the subsequent coagulation reactions. Platelets and in turn FV, FVIII, and FXI are activated. Subsequently, FVIIIa binds to FIXa to form the intrinsic tenase complex, which is aided by a cofactor, FVIIIa, and activates FX at a rate 50-times higher than that of the extrinsic tenase complex, thereby amplifying thrombin generation. Thrombin cleaves fibrinogen into one fibrin monomer and two fibrinopeptides. Fibrin monomers aggregate, crosslink, and branch into an insoluble fibrin network structure. The contact activation system is initiated by FXII, which is activated upon exposure to negatively charged surfaces. Coagulation is driven by FXIIa-mediated FXI cleavage. FXIa activates FIX, which forms an intrinsic tenase complex, eventually leading to thrombin formation. The contact activation system is considered to contribute to thrombosis but is not required for hemostasis in vivo.