Coagulation cascade — tissue-factor initiation, FXI/FIX amplification, prothrombinase, fibrin formation and cross-linking, with the plasma anticoagulant brakes

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The only integral-membrane, non-proteolysed member of the cascade. Binding of tissue factor converts factor VIIa, which has very weak activity on its own, into a potent activator of factors X and IX; F3 carries contributes_to serine-type endopeptidase activity (GO:0004252, IDA) for this complex and also phospholipid binding (GO:0005543, IDA).

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Vitamin K-dependent serine protease; essentially inactive until bound to tissue factor, after which it cleaves both factor X and factor IX. The dual substrate specificity is what lets the extrinsic route feed the intrinsic tenase as well as prothrombinase.

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Entry point of the amplification loop and the boundary of this module: factor XI is activated by factor XIIa of the contact system, by thrombin, and by factor XIa itself. Unusually for the cascade it is a disulfide-linked dimer and is not vitamin K-dependent.

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Catalytic subunit of the intrinsic tenase. Activated by two sequential cleavages (by factor XIa or by the extrinsic tenase); its calcium- and phospholipid-binding Gla and EGF domains hold it on the membrane.

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Non-enzymatic cofactor; thrombin cleavage converts the procofactor factor VIII into factor VIIIa, which assembles with factor IXa and raises factor X activation to physiologically useful rates. Its loss causes haemophilia A.

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Included only in its factor VIII carrier role, which is the edge the RGD diagram draws (F8 associated with Vwf): VWF binds factor VIII through its D'D3 region, keeps it in circulation and delivers it to the injury site, and thrombin then releases factor VIIIa. VWF's platelet-adhesion functions belong to primary haemostasis, outside this module; see its gene review.

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The amplifying feedback arm of thrombin, distinct from its fibrinogen-cleaving and protein C-activating activities modelled in parts 5, 6 and 7. Factor V is activated by both thrombin and factor Xa.

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Convergence point of the extrinsic and intrinsic routes; the catalytic subunit of prothrombinase, held on the anionic phospholipid surface by its Gla domain (F10 also carries phospholipid binding, GO:0005543, IDA).

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Non-enzymatic cofactor activated by thrombin and factor Xa; it both accelerates prothrombin cleavage and redirects it to give thrombin rather than prethrombin 2 as the main product. It is the target of activated protein C.

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The terminal protease of the cascade in its clot-forming role. Cleavage of fibrinopeptide A initiates polymerisation; the slower release of fibrinopeptide B exposes a second polymerisation site.

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Carries fibrinopeptide A, whose removal starts polymerisation, and contributes the alphaC regions to the clot. Fibrinogen is thrombin's substrate, but building the network is fibrinogen's own work, so its role here is structural, not proteolytic.

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Carries fibrinopeptide B, released more slowly than FPA, and the beta15-42 sequence exposed by cleavage.

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Supplies the glutamine and lysine partners that factor XIIIa joins: assembly aligns gamma-chain pairs antiparallel, and cross-linking them gives the gamma-dimers of a stabilised clot. This is the one place where a substrate of the cross-linking reaction also positions the residues it donates.

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Thrombin cleavage of the A subunit activation peptide is the main route to factor XIIIa; factor XIII is activated in the last stage of coagulation, on the fibrin it will cross-link.

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The only transferase in the cascade: a calcium-dependent transglutaminase that ligates gamma-chain pairs and then alpha chains, determining clot viscoelasticity and resistance to fibrinolysis.

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Non-catalytic subunit of the plasma A2B2 tetramer; it carries the A subunit in plasma, keeps it from being activated prematurely, and dissociates on activation. No molecular function is asserted: GOA gives F13B only the fibrin-clot-formation process (IDA), and GO has no term for this carrier role.

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Suicide-substrate serpin and the broadest brake in the system, hitting three of the module's proteases. Heparin or endothelial heparan sulfate accelerates it, allosterically for factor Xa and by bridging for thrombin — the basis of heparin therapy.

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Kunitz-type inhibitor that needs catalytically active factor Xa to quench the factor VIIa-tissue factor complex, and inhibits factor Xa in its own right; this is why extrinsic initiation is self-limiting and amplification is required. GOA gives the parent endopeptidase inhibitor activity (GO:0004866, TAS) and the serine-type child by IBA; both targets are serine proteases, so the child is used here.

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Endothelial membrane cofactor that binds thrombin and converts it from a procoagulant protease into an activator of protein C, raising the rate of protein C activation by orders of magnitude. This is a cofactor role like those of F3, F5 and F8, which this module gives endopeptidase activator activity. GO:0038023 signaling receptor activity is kept here only because thrombomodulin's IDA annotation and all four cached protein C GO-CAMs use it; it does not describe a signal-transducing step.

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Thrombin's anticoagulant face: bound to thrombomodulin it cleaves protein C, turning the cascade's end product into the trigger of its own shutdown.

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Vitamin K-dependent protease that removes the two cofactors the cascade cannot work without, cleaving factor Va at Arg306 and Arg506 and factor VIIIa in its heavy chain. Its loss or resistance of factor V to its cleavage causes thrombophilia.

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Vitamin K-dependent, non-enzymatic cofactor that accelerates APC-catalysed inactivation of factor Va on a phospholipid surface, and also assists TFPI. Not on the RGD curated gene list but drawn in the textbook protein C pathway (RGD's own PW:0000480) and named in the PW:0000474 description as the protein S component of that pathway.

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Serpin whose inhibition of factor Xa is fast only when protein Z, calcium and a phospholipid surface are present, forming a ternary factor Xa-PZ-ZPI complex at the membrane.

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Vitamin K-dependent protein with a protease-like but catalytically degenerate domain; it tethers ZPI and factor Xa to the phospholipid surface. No molecular function is asserted: GOA offers only protein binding and an IBA serine-type endopeptidase activity that is implausible for a pseudoprotease, and GO has no term for this membrane-cofactor role.