Blood Res.  2024;59:35. 10.1007/s44313-024-00040-8.

Back to basics: the coagulation pathway

• Park S
• Park JK

• KMID: 2562539
• DOI: http://doi.org/10.1007/s44313-024-00040-8

Abstract

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.

Keyword

Coagulation; Coagulation pathway; Hemostasis

Figure

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  Fig. 1 Basic concept of blood coagulation. TF-FVIIa forms the extrinsic tenase complex and activates FIX to FIXa as well as FX to FXa. FXa-FVa forms the prothrombinase complex and converts prothrombin to thrombin. At this initiation stage of coagulation, only small amounts of thrombin are generated due to the low circulating levels of FVa. The generated thrombin, although in minor quantities, is sufficient to prime the subsequent coagulation reactions. The platelets as well as FV, FVIII, and FXI are activated. Subsequently, FVIIIa binds FIXa to form the intrinsic tenase complex, which activates FX at a 50-fold higher rate than that by the extrinsic tenase complex, thereby amplifying thrombin generation. Thrombin then cleaves fibrinogen into a fibrin monomer and two fibrinopeptides. Fibrin monomers aggregate, cross-link, and branch into an insoluble fibrin network structure. The intrinsic, contact activation system is initiated by FXII, which is activated when exposed to negatively charged surfaces. The initial step involves activation of plasma prekallikrein to kallikrein, and kallikrein reciprocally activates additional FXII molecules. Coagulation is driven by FXIIa-mediated cleavage of FXI. FXIa activates FIX, which can form intrinsic tenase complex with FVIIIa, eventually leading to thrombin formation. While the contact activation system contributes to thrombosis, it is not required for hemostasis

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  Fig. 2 Regulation of blood coagulation. Antithrombin, tissue factor pathway inhibitor (TFPI), and activated protein C (APC) play major roles in the regulation of blood coagulation reactions. Antithrombin inhibits thrombin, FXa, FIXa, FXIa, and FXIIa when stimulated by physiologic heparan sulfate or pharmacologic heparins. TFPI neutralizes proteases of the extrinsic coagulation pathway, FVIIa, and FXa. APC exerts multiple protective homeostatic actions, including proteolytic inactivation of cofactors, Va and VIIIa, as well as direct cell-signalling activities involving protease-activated receptors (PAR) 1 and 3 and endothelial protein C receptor (EPCR). Protein Z-dependent protease inhibitor (PZI) inhibits FXa and XIa. The PZI-dependent inhibition of factor Xa is enhanced in the presence of protein Z

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