Reactome | Coagulation pathway

Coagulation pathway

Stable Identifier

R-HSA-9769740

Type

Pathway

Species

Homo sapiens

Synonyms

Formation of fibrin clot, Coagulation cascade

ReviewStatus

3/5

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This Reactome module describes the cell-based model of the coagulation pathway (reviewed by Hoffman M & Monroe DM 2001; Hoffman M 2003; Smith SA 2009; O'Donnell JS et al., 2019). This model describes the intricate interactions between various coagulation factors that, under normal physiologic conditions, occur on membrane surfaces of activated cells at the site of vessel injury. The cell-based model consists of several overlapping stages (reviewed by Hoffman M & Monroe DM 2001; Hoffman M 2003; Roberts HR et al., 2006; Smith SA 2009; O'Donnell JS et al., 2019):

Initiation phase, which proceeds through the formation of the activated tissue factor (TF) : factor VIIa (FVIIa) complex and TF:FVIIa-mediated generation of a small amount of thrombin (FII) on the membrane surfaces of TF-bearing cells (e.g., fibroblasts, pericytes) (reviewed by Grover SP & Mackman N 2018).

Amplification phase, which is mediated by the small amount of thrombin produced in the TF-mediated initiation phase (reviewed by O'Donnell JS et al., 2019). On the platelet surface, thrombin activates factor XI (FXI), factor VIII (FVIII) and factor V (FV). The activated FXI (FXIa) converts factor IX (FIX) to FIXa, which binds the co-factor FVIIIa. The FIXa:FVIIIa complex (the tenase complex) generates activated factor X (FXa) (activated FX) which in turn binds FVa to form the FXa:FVa (prothrombinase) complex. The FXa:FVa complex converts prothrombin (FII) to thrombin (FIIa), which activates more FXI, FVIII and FV creating a positive feedback cycle. Additionally, interactions of FIIa with platelet surface receptors such as surface protease-activated receptors (PARs) contribute to the platelet's activation and degranulation, and the recruitment of additional platelets to the site of injury, where activated platelets aggregate to form the platelet plug (Swieringa F et al., 2018; Sang Y et al., 2021). Activated procoagulant platelets also release clotting factors and expose phosphatidylserine (PS) on their cell membranes providing a surface for the assembly of the tenase and prothrombinase complexes (Swieringa F et al., 2018; Sang Y et al., 2021).

Propagation phase, which occurs on the activated platelet surface, generates large amounts of thrombin via FXa:FVa-catalyzed cleavage of prothrombin.

In the final phase of clotting, thrombin produced through amplification and propagation stages converts soluble fibrinogen into fibrin, which polymerizes to form insoluble fibrin fibers that are crosslinked by thrombin-activated factor XIII (FXIIIa) to stabilize the platelet plug.

Each of these coagulation stages is tightly controlled by endogenous regulators to prevent excessive clotting that may lead to a pathologic thrombus formation (reviewed by Dahlbäck B 2023). In this module we describe several natural anticoagulants including tissue factor pathway inhibitor (TFPI), protein C, protein S, thrombomodulin (TM) and antithrombin III. TFPI can form a quaternary complex with FXa, FVIIa and TF, effectively inactivating these clotting factors to restrict coagulation (Mast AE 2015; Mehic D et al., 2021). Protein C is activated by the thrombin:thrombomodulin complex on intact endothelial cells and along with cofactor protein S, inhibits coagulation process by deactivating FVa and FVIIIa (reviewed by Ikezoe T 2015; Alshehri FS et al., 2024). Heparan sulfate-bound antithrombin III (SERPINC1) forms a complex with thrombin and other clotting factors such as FXa and FXIa to prevent clot formation (Zhang W et al., 2005; reviewed by Rezaie AR et al., 2020).

Literature References

PubMed ID	Title	Journal	Year
30919939	Advances in understanding the molecular mechanisms that maintain normal haemostasis O'Donnell, JS, O'Sullivan, JM, Preston, RJS	Br J Haematol	2019