id: MODULE:coagulation_cascade title: Coagulation cascade — tissue-factor initiation, FXI/FIX amplification, prothrombinase, fibrin formation and cross-linking, with the plasma anticoagulant brakes description: >- The coagulation cascade converts a local vascular injury into an insoluble, cross-linked fibrin clot through a chain of limited proteolytic activations of circulating zymogens and their non-enzymatic protein cofactors. Initiation is extrinsic: tissue factor (F3), an integral membrane protein exposed at the injury site, binds factor VII/VIIa (F7) and the resulting extrinsic tenase complex cleaves both factor X (F10) and factor IX (F9). The small amount of thrombin this generates feeds back to activate the cofactors factor V (F5) and factor VIII (F8) and the zymogen factor XI (F11), switching the system into its amplification mode: factor XIa activates factor IX, and factor IXa together with factor VIIIa forms the intrinsic tenase that sustains factor Xa production. Factor VIII circulates bound to von Willebrand factor (VWF), which carries it and protects it from clearance until thrombin releases it. The pathways converge on the prothrombinase complex, factor Xa with its cofactor factor Va on a procoagulant phospholipid surface, which raises the rate of prothrombin (F2) activation by several orders of magnitude. Thrombin then cleaves fibrinopeptides from fibrinogen (FGA, FGB, FGG); the fibrin monomers polymerise into a branched network by their own end-to-middle and lateral associations, and thrombin-activated factor XIII (the catalytic A subunit F13A1 with its carrier B subunit F13B) covalently cross-links the gamma chains, stabilising the clot and making it resistant to lysis. The same proteases are held in check by plasma anticoagulants: antithrombin (SERPINC1) traps thrombin, factor Xa and factor IXa; tissue factor pathway inhibitor (TFPI) shuts down the extrinsic tenase and factor Xa; the protein C pathway, in which thrombin bound to endothelial thrombomodulin (THBD) activates protein C (PROC) and activated protein C with its cofactor protein S (PROS1) destroys factors Va and VIIIa, removes the cofactors the cascade depends on; and protein Z-dependent protease inhibitor (SERPINA10) with protein Z (PROZ) inactivates factor Xa at the membrane surface. Most of the proteases and protein C, S and Z are vitamin K-dependent, their Gla domains anchoring them to the anionic phospholipid surface. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000474 title: coagulation cascade pathway statement: >- The module boundary, its members and its topology follow the RGD interactive diagram for this Pathway Ontology term. The diagram draws F3 associated with F7a, F10 associated with the TF/F7a complex, the TF/F7a complex activating F10a and F9a, F12a activating F11a, F11a activating F9a, F9a activating F8a, the tenase complex activating F10a, the prothrombinase complex activating F2a, F2a acting on fibrinogen and on fibrin, pF13 activating pF13a, pF13a driving fibrin polymerization and cross-linking, F8 associated with Vwf, and the anticoagulant arms Tfpi (on the extrinsic tenase complex), Serpinc1 (on F2a, F9a and F10a), activated protein C (on F5a and F8a), and Proz associated with Serpina10 (on F10a). Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000474.yaml). - source_id: PW:0000480 title: protein C anticoagulant pathway statement: >- The module's protein C part also covers this RGD pathway, which PW defines as activated protein C, aided by protein S, inactivating F8a and F5a. Five of its six RGD human genes are members here (F2, F5, PROC, PROS1, THBD). The endothelial protein C receptor (PROCR), which presents protein C to the thrombin-thrombomodulin complex, is not modelled. - source_id: GO:0072378 title: blood coagulation, fibrin clot formation statement: >- The module is grounded in GO blood coagulation, fibrin clot formation, which is also the PW->GO candidate mapping recorded for PW:0000474 in the project's seed table. Its three GO children — blood coagulation, extrinsic pathway (GO:0007598), intrinsic pathway (GO:0007597) and common pathway (GO:0072377) — correspond to the module's initiation, amplification and prothrombinase parts, so the parent is the most specific term covering the whole module. - source_id: GO:0030195 title: negative regulation of blood coagulation statement: >- The regulatory part of the module (antithrombin, TFPI, the protein C pathway and protein Z/ZPI) is grounded in negative regulation of blood coagulation, the process term carried experimentally by F2 (IDA), PROC (IDA), THBD (IDA) and TFPI (IDA). - source_id: gomodel:666b894f00000232 title: Thrombin-Thrombomodulin pair activating Protein C activation (Human) statement: >- A curator-built human GO-CAM (cached under gocams/666b894f00000232/) models the protein C arm of this module with matching molecular functions: THBD signaling receptor activity (GO:0038023) at the plasma membrane regulating F2 serine-type endopeptidase activity (GO:0004252), which in turn is causally upstream of PROC serine-type endopeptidase activity (GO:0004252), all part of negative regulation of blood coagulation (GO:0030195) in the extracellular region. Three sibling models (gomodel:665912ed00003542, gomodel:665912ed00003594, gomodel:666b894f00000010) carry the same three activities with different upstream thrombomodulin partners. No cached production GO-CAM covers the procoagulant steps of this module. - source_id: PMID:3422166 title: "The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action." statement: >- States the extrinsic initiation step and the dual target of TFPI, which together set the module's first part and its first anticoagulant brake. supporting_text: Blood coagulation is initiated when plasma factor VII(a) binds to its essential cofactor tissue factor (TF) and proteolytically activates factors X and IX. - source_id: PMID:8083241 title: A model for the tissue factor pathway to thrombin. I. An empirical study. statement: >- Reconstitution of the whole tissue-factor pathway at plasma concentrations: the lag before explosive thrombin generation is the interval of cofactor (FV, FVIII) activation, establishing the feedback part of this module as rate-controlling. supporting_text: The lag was a function of tissue factor/factor VIIa concentration and represented primarily the interval of factor V and factor VIII activation. - source_id: PMID:16102057 title: Fibrinogen and fibrin structure and functions. statement: >- Defines the output steps: thrombin cleaves fibrinopeptide A to start polymerisation, the fibrils themselves build the network, and factor XIII(a) cross-links the gamma chains. supporting_text: Fibrin is formed after thrombin cleavage of fibrinopeptide A (FPA) from fibrinogen Aalpha-chains, thus initiating fibrin polymerization. - source_id: PMID:21742792 title: "Factor XIII: a coagulation factor with multiple plasmatic and cellular functions." statement: >- Places factor XIII as the last step of the cascade and names its substrate state (insoluble fibrin), supporting the clot-stabilisation part. supporting_text: it is a protransglutaminase, which becomes activated in the last stage of coagulation notes: >- Derived from the RGD Pathway Ontology diagram PW:0000474 through the RGD_PATHWAY_ONTOLOGY project. The diagram supplied the boundary, members and topology; GO terms were then chosen against each protein's experimental GOA annotations in QuickGO (F7 GO:0004252 TAS and contributes_to IDA; F9 GO:0004252 EXP; F10 GO:0004252 IDA; F11 GO:0004252 TAS with GO:0031638 zymogen activation IDA; F2 GO:0004252 IDA with GO:0030194 and GO:0030195 IDA; PROC GO:0004252 IMP/TAS; F13A1 GO:0003810 IDA with GO:0018149 IDA; FGA, FGB and FGG GO:0005198 IDA with GO:0072378 IDA; VWF GO:0140597 from its gene review; SERPINC1 and SERPINA10 GO:0004867; THBD GO:0038023 IDA). Four cofactor roles have no supporting molecular function in GOA and are asserted here as curator judgment, flagged rather than hidden. Tissue factor (F3), factor Va (F5) and factor VIIIa (F8) are given endopeptidase activator activity (GO:0061133): each is a non-enzymatic protein cofactor whose only job is to raise the catalytic efficiency of a partner serine protease by orders of magnitude (PMID:7350159, PMID:6782101), and F3 already carries contributes_to serine-type endopeptidase activity (GO:0004252, IDA PMID:24998411) for the same complex. Protein S (PROS1) is given peptidase activator activity (GO:0016504) because it accelerates APC-catalysed factor Va inactivation (PMID:6892911); its only GOA molecular function is protein binding, which this project does not use. Protein Z (PROZ) is left without a molecular function: it is the membrane cofactor in the factor Xa-PZ-ZPI complex (PMID:9689066) and no GO term describes that role, while its IBA GO:0004252 is implausible for a protein with a degenerate catalytic triad; this is recorded as a doubt rather than corrected here. Factor XIII B subunit (F13B) is likewise functionless, carrying only the fibrin-clot-formation process it has by IDA, because its role is to carry and stabilise the A subunit. Thrombomodulin keeps the GO:0038023 signaling receptor activity for consistency with its IDA annotation and the four cached protein C GO-CAMs; the annoton's role description states that the term does not describe its cofactor role. Fibrinogen follows the substrate-versus-participant rule: it is thrombin's substrate, but the polymerisation and network formation are its own work, so FGA, FGB and FGG are modelled with structural molecule activity and the fibrin-clot-formation and protein-polymerization processes they carry by IDA, not with any protease term. Deliberately outside this module. Contact activation (F12, KLKB1, KNG1) belongs to modules/kallikrein_kinin_cascade.yaml; it is drawn on the RGD diagram and is retained here only as the upstream connection into FXI activation (F12a activating F11), which the revised model of coagulation shows is also, and in vivo mainly, performed by thrombin (PMID:1652157). Fibrinolysis (PLG, PLAT and partners) belongs to modules/fibrinolysis.yaml, which takes cross-linked fibrin from this module as its input. The vitamin K cycle (GGCX, VKORC1) is cofactor supply for the Gla domains of F2, F7, F9, F10, PROC, PROS1 and PROZ and is a separate module; platelet activation and the protease-activated receptors (F2R, F2RL1, F2RL2, F2RL3) are downstream signalling outputs, not steps of fibrin formation. SERPING1 (C1 inhibitor) is on the RGD gene list but its coagulation targets are FXIIa, FXIa and kallikrein — the contact system — so it is placed with modules/kallikrein_kinin_cascade.yaml; its action on FXIa partly overlaps this module and is noted there. APOH (beta-2-glycoprotein I) appears in RGD's wider gene list for this pathway but is an anionic-phospholipid-binding plasma protein best known as the antiphospholipid-antibody antigen, not a step in the cascade, and is excluded. Gene reviews exist only for VWF (and APOH); the remaining twenty members are unreviewed, which is a curation gap recorded in the project plan rather than a knowledge gap here. module: id: coagulation_cascade label: Blood coagulation cascade module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: blood coagulation, fibrin clot formation term: id: GO:0072378 label: blood coagulation, fibrin clot formation description: >- Sequential limited proteolysis of plasma zymogens and their cofactors, ending in a cross-linked fibrin clot. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: >- Members are grounded on the human proteins; the cascade is conserved across jawed vertebrates. cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region description: Blood plasma, where the zymogens and inhibitors circulate. - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane description: >- The anionic phospholipid surface (injured vessel wall, activated platelet, endothelium) on which tissue factor, the tenases and prothrombinase assemble. parts: - order: 1 role: extrinsic initiation node: id: coag_extrinsic_initiation label: Tissue factor-factor VIIa complex activation of factor X and factor IX module_type: REACTION description: >- Tissue factor exposed at the site of injury binds factor VII/VIIa; the extrinsic tenase complex then cleaves factor X to factor Xa and factor IX to factor IXa, generating the first, small burst of thrombin. concepts: - preferred_term: blood coagulation, extrinsic pathway term: id: GO:0007598 label: blood coagulation, extrinsic pathway annotons: - id: f3_tissue_factor label: Tissue factor cofactor activity in the extrinsic tenase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F3 term: id: UniProtKB:P13726 label: Tissue factor function: preferred_term: endopeptidase activator activity term: id: GO:0061133 label: endopeptidase activator activity targets: - preferred_term: coagulation factor VII/VIIa term: id: UniProtKB:P08709 label: Coagulation factor VII processes: - preferred_term: blood coagulation, extrinsic pathway term: id: GO:0007598 label: blood coagulation, extrinsic pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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). evidence: - source_id: PMID:3422166 statement: >- Tissue factor is the essential cofactor of factor VII(a) in the initiating step. supporting_text: Blood coagulation is initiated when plasma factor VII(a) binds to its essential cofactor tissue factor (TF) and proteolytically activates factors X and IX. - id: f7_extrinsic_tenase label: Factor VIIa proteolytic activation of factors X and IX participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F7 term: id: UniProtKB:P08709 label: Coagulation factor VII function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: coagulation factor X term: id: UniProtKB:P00742 label: Coagulation factor X - preferred_term: coagulation factor IX term: id: UniProtKB:P00740 label: Coagulation factor IX processes: - preferred_term: blood coagulation, extrinsic pathway term: id: GO:0007598 label: blood coagulation, extrinsic pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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. evidence: - source_id: PMID:271951 statement: >- The tissue factor-factor VII reaction product activates factor IX, and factor IXa then activates factor X — a route that bypasses factor XIa. supporting_text: The reaction product of tissue factor and Factor VII functioned as a potent Factor IX activator in the assay system used. Activated Factor IX itself activated Factor X; thrombin failed to activate Factor IX. - source_id: PMID:3422166 statement: Factor VII(a)-tissue factor proteolytically activates factors X and IX. supporting_text: Blood coagulation is initiated when plasma factor VII(a) binds to its essential cofactor tissue factor (TF) and proteolytically activates factors X and IX. - order: 2 role: intrinsic amplification node: id: coag_intrinsic_amplification label: Factor XIa-factor IXa-factor VIIIa amplification of factor X activation module_type: REACTION description: >- Factor XIa activates factor IX; factor IXa with its thrombin-activated cofactor factor VIIIa forms the intrinsic tenase on the phospholipid surface and sustains factor Xa generation far beyond what the extrinsic route provides. Factor VIII reaches this step as a complex with von Willebrand factor. concepts: - preferred_term: blood coagulation, intrinsic pathway term: id: GO:0007597 label: blood coagulation, intrinsic pathway annotons: - id: f11_fix_activation label: Factor XIa activation of factor IX participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F11 term: id: UniProtKB:P03951 label: Coagulation factor XI function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: coagulation factor IX term: id: UniProtKB:P00740 label: Coagulation factor IX processes: - preferred_term: blood coagulation, intrinsic pathway term: id: GO:0007597 label: blood coagulation, intrinsic pathway - preferred_term: zymogen activation term: id: GO:0031638 label: zymogen activation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:1652157 statement: >- Thrombin, not only factor XIIa, activates factor XI, and factor XIa autoactivation contributes. supporting_text: A revised model of coagulation is proposed in which factor XI is activated by thrombin. In the absence of cofactors, thrombin is more effective (kcat/Km = 1.6 x 10(5)) than factor XIIa (1.7 x 10(4)) in activating factor XI. - id: f9_intrinsic_tenase label: Factor IXa proteolytic activation of factor X participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F9 term: id: UniProtKB:P00740 label: Coagulation factor IX function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: coagulation factor X term: id: UniProtKB:P00742 label: Coagulation factor X cofactors: - preferred_term: coagulation factor VIIIa term: id: UniProtKB:P00451 label: Coagulation factor VIII processes: - preferred_term: blood coagulation, intrinsic pathway term: id: GO:0007597 label: blood coagulation, intrinsic pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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. evidence: - source_id: PMID:6782101 statement: >- Factor IXa activates factor X, and the reaction was characterised with and without its cofactor factor VIIIa and phospholipid. supporting_text: The kinetic parameters of bovine factor X activation by bovine factor IXa have been determined in the absence and presence of Ca2+, thrombin-activated bovine factor VIII (VIIIa), and phospholipid - id: f8_tenase_cofactor label: Factor VIIIa cofactor activity in the intrinsic tenase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F8 term: id: UniProtKB:P00451 label: Coagulation factor VIII function: preferred_term: endopeptidase activator activity term: id: GO:0061133 label: endopeptidase activator activity targets: - preferred_term: coagulation factor IXa term: id: UniProtKB:P00740 label: Coagulation factor IX processes: - preferred_term: blood coagulation, intrinsic pathway term: id: GO:0007597 label: blood coagulation, intrinsic pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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. evidence: - source_id: PMID:3082357 statement: >- Thrombin proteolysis generates the factor VIIIa fragments and this correlates with maximum coagulant activity. supporting_text: Maximum coagulant activity of thrombin-activated factor VIII was correlated with the generation of these polypeptides. - source_id: PMID:6782101 statement: >- Factor VIIIa is the cofactor whose presence defines the intrinsic tenase reaction studied here. supporting_text: thrombin-activated bovine factor VIII (VIIIa) - id: vwf_fviii_carrier label: von Willebrand factor carriage of factor VIII participant: selector_type: GENE_PRODUCT gene_product: preferred_term: VWF term: id: UniProtKB:P04275 label: von Willebrand factor function: preferred_term: protein carrier chaperone term: id: GO:0140597 label: protein carrier chaperone cargo: - preferred_term: coagulation factor VIII term: id: UniProtKB:P00451 label: Coagulation factor VIII locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:9759493 statement: >- VWF is the carrier of factor VIII and this interaction is needed for normal factor VIII survival in plasma. supporting_text: VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. - order: 3 role: thrombin feedback activation of cofactors and factor XI node: id: coag_thrombin_feedback label: Thrombin feedback activation of factor V, factor VIII and factor XI module_type: REGULATORY_STEP description: >- The trace thrombin made during initiation cleaves the procofactors factor V and factor VIII to factor Va and factor VIIIa and activates factor XI, converting a slow initiation into explosive propagation. The lag phase of thrombin generation is essentially the time taken by this step. annotons: - id: f2_cofactor_feedback label: Thrombin activation of factor V, factor VIII and factor XI participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F2 term: id: UniProtKB:P00734 label: Prothrombin function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: coagulation factor V term: id: UniProtKB:P12259 label: Coagulation factor V - preferred_term: coagulation factor VIII term: id: UniProtKB:P00451 label: Coagulation factor VIII - preferred_term: coagulation factor XI term: id: UniProtKB:P03951 label: Coagulation factor XI processes: - preferred_term: positive regulation of blood coagulation term: id: GO:0030194 label: positive regulation of blood coagulation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:8083241 statement: >- In a reconstituted tissue-factor pathway the lag before propagation is the interval of factor V and factor VIII activation, and factor V is activated by both factor Xa and thrombin. supporting_text: Analyses of the activation pattern of factor V indicated that the cofactor is activated by both factor Xa and thrombin which are formed at low levels during the lag phase of the reaction. - source_id: PMID:8083241 statement: Without factor V no thrombin is formed; the cofactors are obligatory. supporting_text: When factor V was deleted from the reaction mixture, no thrombin formation was observed. - source_id: PMID:1652157 statement: Thrombin activates factor XI more efficiently than factor XIIa does. supporting_text: In the absence of cofactors, thrombin is more effective (kcat/Km = 1.6 x 10(5)) than factor XIIa (1.7 x 10(4)) in activating factor XI. - source_id: PMID:3082357 statement: Thrombin cleavage activates factor VIII. supporting_text: Maximum coagulant activity of thrombin-activated factor VIII was correlated with the generation of these polypeptides. - order: 4 role: common pathway — prothrombin activation node: id: coag_prothrombinase label: Prothrombinase (factor Xa-factor Va) activation of prothrombin module_type: REACTION description: >- Factor Xa, with factor Va, calcium and a procoagulant phospholipid surface, forms the prothrombinase complex and cleaves prothrombin to thrombin. The assembled complex is some three orders of magnitude faster than factor Xa alone and shifts the reaction pathway so that thrombin, rather than the prethrombin 2 intermediate, is the product. concepts: - preferred_term: blood coagulation, common pathway term: id: GO:0072377 label: blood coagulation, common pathway annotons: - id: f10_prothrombinase label: Factor Xa proteolytic activation of prothrombin participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F10 term: id: UniProtKB:P00742 label: Coagulation factor X function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: prothrombin term: id: UniProtKB:P00734 label: Prothrombin cofactors: - preferred_term: coagulation factor Va term: id: UniProtKB:P12259 label: Coagulation factor V processes: - preferred_term: blood coagulation, common pathway term: id: GO:0072377 label: blood coagulation, common pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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). evidence: - source_id: PMID:7350159 statement: >- The complete prothrombinase complex activates prothrombin with a Vmax about three orders of magnitude above factor Xa alone. supporting_text: For the complete prothrombinase complex (Xa, Va, Ca2+, and 7.5 microM phospholipid), a Km for prothrombin of 0.21 microM and a Vmax of 1919 mol min-1 mol of Xa-1 is found. - id: f5_prothrombinase_cofactor label: Factor Va cofactor activity in prothrombinase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F5 term: id: UniProtKB:P12259 label: Coagulation factor V function: preferred_term: endopeptidase activator activity term: id: GO:0061133 label: endopeptidase activator activity targets: - preferred_term: coagulation factor Xa term: id: UniProtKB:P00742 label: Coagulation factor X processes: - preferred_term: blood coagulation, common pathway term: id: GO:0072377 label: blood coagulation, common pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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. evidence: - source_id: PMID:7350159 statement: >- Factor Va changes the product distribution of prothrombin activation to thrombin. supporting_text: In the presence of factor Va, thrombin is the main end product and minute amounts of prethrombin 2 are formed. - order: 5 role: fibrin formation node: id: coag_fibrin_formation label: Thrombin cleavage of fibrinogen and fibrin polymerisation module_type: REACTION description: >- Thrombin removes fibrinopeptides A and B from the fibrinogen Aalpha and Bbeta chains; the resulting fibrin monomers self-assemble into double-stranded fibrils that associate laterally and branch into the clot network. annotons: - id: f2_fibrinogen_cleavage label: Thrombin cleavage of fibrinogen participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F2 term: id: UniProtKB:P00734 label: Prothrombin function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: fibrinogen alpha chain term: id: UniProtKB:P02671 label: Fibrinogen alpha chain - preferred_term: fibrinogen beta chain term: id: UniProtKB:P02675 label: Fibrinogen beta chain processes: - preferred_term: blood coagulation, fibrin clot formation term: id: GO:0072378 label: blood coagulation, fibrin clot formation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:16102057 statement: >- Thrombin cleavage of fibrinopeptide A from the Aalpha chains initiates fibrin polymerisation. supporting_text: Fibrin is formed after thrombin cleavage of fibrinopeptide A (FPA) from fibrinogen Aalpha-chains, thus initiating fibrin polymerization. - id: fga_fibrin_polymer label: Fibrinogen alpha chain in fibrin network assembly participant: selector_type: GENE_PRODUCT gene_product: preferred_term: FGA term: id: UniProtKB:P02671 label: Fibrinogen alpha chain function: preferred_term: structural molecule activity term: id: GO:0005198 label: structural molecule activity processes: - preferred_term: blood coagulation, fibrin clot formation term: id: GO:0072378 label: blood coagulation, fibrin clot formation - preferred_term: protein polymerization term: id: GO:0051258 label: protein polymerization locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:16102057 statement: >- Fibrils assemble by the fibrin molecules' own end-to-middle and lateral associations to create the clot network. supporting_text: Double-stranded fibrils form through end-to-middle domain (D:E) associations, and concomitant lateral fibril associations and branching create a clot network. - id: fgb_fibrin_polymer label: Fibrinogen beta chain in fibrin network assembly participant: selector_type: GENE_PRODUCT gene_product: preferred_term: FGB term: id: UniProtKB:P02675 label: Fibrinogen beta chain function: preferred_term: structural molecule activity term: id: GO:0005198 label: structural molecule activity processes: - preferred_term: blood coagulation, fibrin clot formation term: id: GO:0072378 label: blood coagulation, fibrin clot formation - preferred_term: protein polymerization term: id: GO:0051258 label: protein polymerization locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Carries fibrinopeptide B, released more slowly than FPA, and the beta15-42 sequence exposed by cleavage. evidence: - source_id: PMID:16102057 statement: >- Each fibrinogen molecule is built from disulfide-bridged Aalpha, Bbeta and gamma chains, so all three genes contribute to the polymer. supporting_text: Fibrinogen molecules are comprised of two sets of disulfide-bridged Aalpha-, Bbeta-, and gamma-chains. - id: fgg_fibrin_polymer label: Fibrinogen gamma chain in fibrin network assembly and cross-linking participant: selector_type: GENE_PRODUCT gene_product: preferred_term: FGG term: id: UniProtKB:P02679 label: Fibrinogen gamma chain function: preferred_term: structural molecule activity term: id: GO:0005198 label: structural molecule activity processes: - preferred_term: blood coagulation, fibrin clot formation term: id: GO:0072378 label: blood coagulation, fibrin clot formation - preferred_term: protein polymerization term: id: GO:0051258 label: protein polymerization locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:16102057 statement: >- Fibrin assembly aligns gamma-chain pairs that factor XIII or XIIIa then cross-links into gamma-dimers. supporting_text: Fibrin assembly facilitates intermolecular antiparallel C-terminal alignment of gamma-chain pairs, which are then covalently 'cross-linked' by factor XIII ('plasma protransglutaminase') or XIIIa to form 'gamma-dimers'. - order: 6 role: clot stabilisation by cross-linking node: id: coag_fibrin_crosslinking label: Factor XIII activation and cross-linking of fibrin module_type: REACTION description: >- Thrombin activates plasma factor XIII, a tetramer of two catalytic A subunits and two carrier B subunits; factor XIIIa then forms epsilon-(gamma-glutamyl)lysine bonds between fibrin chains, stabilising the clot and protecting it from lysis. annotons: - id: f2_f13_activation label: Thrombin activation of plasma factor XIII participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F2 term: id: UniProtKB:P00734 label: Prothrombin function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: coagulation factor XIII A chain term: id: UniProtKB:P00488 label: Coagulation factor XIII A chain processes: - preferred_term: blood coagulation, fibrin clot formation term: id: GO:0072378 label: blood coagulation, fibrin clot formation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:21742792 statement: >- Factor XIII is a protransglutaminase activated at the end of the cascade, acting on an insoluble substrate. supporting_text: it is a protransglutaminase, which becomes activated in the last stage of coagulation - id: f13a1_transglutaminase label: Factor XIIIa cross-linking of fibrin participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F13A1 term: id: UniProtKB:P00488 label: Coagulation factor XIII A chain function: preferred_term: protein-glutamine gamma-glutamyltransferase activity term: id: GO:0003810 label: protein-glutamine gamma-glutamyltransferase activity substrates: - preferred_term: fibrin gamma chain term: id: UniProtKB:P02679 label: Fibrinogen gamma chain - preferred_term: fibrin alpha chain term: id: UniProtKB:P02671 label: Fibrinogen alpha chain processes: - preferred_term: peptide cross-linking term: id: GO:0018149 label: peptide cross-linking - preferred_term: blood coagulation, fibrin clot formation term: id: GO:0072378 label: blood coagulation, fibrin clot formation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:21742792 statement: >- Factor XIIIa stabilises the fibrin clot and protects fibrin against fibrinolysis. supporting_text: stabilization of fibrin clot, and protection of fibrin against fibrinolysis - source_id: PMID:16102057 statement: Factor XIII or XIIIa cross-links aligned gamma-chain pairs into gamma-dimers. supporting_text: which are then covalently 'cross-linked' by factor XIII ('plasma protransglutaminase') or XIIIa to form 'gamma-dimers' - id: f13b_carrier label: Factor XIII B subunit carriage of the catalytic A subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F13B term: id: UniProtKB:P05160 label: Coagulation factor XIII B chain processes: - preferred_term: blood coagulation, fibrin clot formation term: id: GO:0072378 label: blood coagulation, fibrin clot formation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:16102057 statement: >- The plasma factor XIII A2B2 complex is the form bound by fibrinogen, which suppresses its cross-linking activity in blood. supporting_text: suppression of plasma factor XIII-mediated cross-linking activity in blood by binding the factor XIII A2B2 complex - order: 7 role: anticoagulant regulation node: id: coag_anticoagulant_regulation label: Plasma anticoagulant systems restraining the cascade module_type: REGULATORY_STEP description: >- Four systems keep the cascade local and self-limiting: antithrombin traps thrombin, factor Xa and factor IXa; tissue factor pathway inhibitor blocks the extrinsic tenase and factor Xa; thrombin bound to endothelial thrombomodulin activates protein C, which with protein S destroys factors Va and VIIIa; and protein Z-dependent protease inhibitor with protein Z inactivates factor Xa at the membrane. concepts: - preferred_term: negative regulation of blood coagulation term: id: GO:0030195 label: negative regulation of blood coagulation annotons: - id: serpinc1_antithrombin label: Antithrombin inhibition of thrombin, factor Xa and factor IXa participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SERPINC1 term: id: UniProtKB:P01008 label: Antithrombin-III function: preferred_term: serine-type endopeptidase inhibitor activity term: id: GO:0004867 label: serine-type endopeptidase inhibitor activity targets: - preferred_term: thrombin term: id: UniProtKB:P00734 label: Prothrombin - preferred_term: coagulation factor Xa term: id: UniProtKB:P00742 label: Coagulation factor X - preferred_term: coagulation factor IXa term: id: UniProtKB:P00740 label: Coagulation factor IX processes: - preferred_term: negative regulation of blood coagulation term: id: GO:0030195 label: negative regulation of blood coagulation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:10497166 statement: >- Heparin activates antithrombin against factor Xa allosterically and against thrombin by a bridging mechanism. supporting_text: A sequence-specific heparin pentasaccharide activates the serpin, antithrombin, to inhibit factor Xa through an allosteric mechanism, whereas full-length heparin chains containing this sequence further activate the serpin to inhibit thrombin by an alternative bridging mechanism. - id: tfpi_extrinsic_brake label: Tissue factor pathway inhibitor shutdown of the extrinsic tenase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TFPI term: id: UniProtKB:P10646 label: Tissue factor pathway inhibitor function: preferred_term: serine-type endopeptidase inhibitor activity term: id: GO:0004867 label: serine-type endopeptidase inhibitor activity targets: - preferred_term: coagulation factor VIIa in the tissue factor complex term: id: UniProtKB:P08709 label: Coagulation factor VII - preferred_term: coagulation factor Xa term: id: UniProtKB:P00742 label: Coagulation factor X processes: - preferred_term: negative regulation of blood coagulation term: id: GO:0030195 label: negative regulation of blood coagulation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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. evidence: - source_id: PMID:3422166 statement: >- Inhibition of tissue factor activity requires factor VIIa, active factor Xa, calcium and the inhibitor, which also inhibits factor Xa directly. supporting_text: This process is reversible and requires the presence of VII(a), catalytically active Xa, Ca2+, and another component that appears to be associated with the lipoproteins in plasma, a lipoprotein-associated coagulation inhibitor (LACI). - source_id: PMID:3422166 statement: The same inhibitor inhibits factor Xa. supporting_text: LACI(HG2) also inhibited Xa with an apparent t1/2 of 50 seconds. - id: thbd_thrombin_switch label: Thrombomodulin redirection of thrombin to protein C activation participant: selector_type: GENE_PRODUCT gene_product: preferred_term: THBD term: id: UniProtKB:P07204 label: Thrombomodulin function: preferred_term: signaling receptor activity term: id: GO:0038023 label: signaling receptor activity processes: - preferred_term: negative regulation of blood coagulation term: id: GO:0030195 label: negative regulation of blood coagulation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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. evidence: - source_id: PMID:7017729 statement: >- The endothelial surface supplies a cofactor that greatly enhances thrombin-catalysed protein C activation. supporting_text: It is proposed that the surface of vascular endothelium provides a cofactor that enhances the rate of protein C activation by thrombin. - source_id: PMID:7017729 statement: Endothelial monolayers accelerate thrombin-catalysed protein C activation. supporting_text: Cultured monolayers of human endothelium enhance the rate of thrombin-catalyzed protein C activation. gocam_associations: - model: gomodel:666b894f00000232 activity: gomodel:666b894f00000232/666b894f00000233 title: THBD signaling receptor activity (GO:0038023), part of GO:0030195, plasma membrane - id: f2_protein_c_activation label: Thrombin activation of protein C participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F2 term: id: UniProtKB:P00734 label: Prothrombin function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: protein C term: id: UniProtKB:P04070 label: Vitamin K-dependent protein C cofactors: - preferred_term: thrombomodulin term: id: UniProtKB:P07204 label: Thrombomodulin processes: - preferred_term: negative regulation of blood coagulation term: id: GO:0030195 label: negative regulation of blood coagulation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Thrombin's anticoagulant face: bound to thrombomodulin it cleaves protein C, turning the cascade's end product into the trigger of its own shutdown. evidence: - source_id: PMID:7017729 statement: >- Protein C is activated by thrombin, and dramatically faster in the presence of the endothelial cofactor. supporting_text: The rate of activated protein C formation during the transit through the myocardium is at least 20,000 times that of thrombin-catalyzed activation of protein C in the perfusion solution. gocam_associations: - model: gomodel:666b894f00000232 activity: gomodel:666b894f00000232/666b894f00000240 title: F2 serine-type endopeptidase activity (GO:0004252) regulated by THBD and upstream of PROC - id: proc_cofactor_inactivation label: Activated protein C inactivation of factors Va and VIIIa participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PROC term: id: UniProtKB:P04070 label: Vitamin K-dependent protein C function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: coagulation factor Va term: id: UniProtKB:P12259 label: Coagulation factor V - preferred_term: coagulation factor VIIIa term: id: UniProtKB:P00451 label: Coagulation factor VIII cofactors: - preferred_term: protein S term: id: UniProtKB:P07225 label: Vitamin K-dependent protein S processes: - preferred_term: negative regulation of blood coagulation term: id: GO:0030195 label: negative regulation of blood coagulation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:9065469 statement: >- In a reconstituted tissue-factor pathway the protein C arm shuts down thrombin generation by inactivating factor Va. supporting_text: Our data thus suggest that the protein C pathway regulates thrombin generation solely by the inactivation of factor Va. - source_id: PMID:3082357 statement: >- Activated protein C cleaves factor VIII, and this cleavage correlates with loss of its coagulant activity. supporting_text: This cleavage correlated with inactivation of factor VIII by APC. gocam_associations: - model: gomodel:666b894f00000232 activity: gomodel:666b894f00000232/666b894f00000248 title: PROC serine-type endopeptidase activity (GO:0004252), part of GO:0030195, with F5 and F8 as inputs - id: pros1_apc_cofactor label: Protein S cofactor activity for activated protein C participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PROS1 term: id: UniProtKB:P07225 label: Vitamin K-dependent protein S function: preferred_term: peptidase activator activity term: id: GO:0016504 label: peptidase activator activity targets: - preferred_term: activated protein C term: id: UniProtKB:P04070 label: Vitamin K-dependent protein C processes: - preferred_term: negative regulation of blood coagulation term: id: GO:0030195 label: negative regulation of blood coagulation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- 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. evidence: - source_id: PMID:6892911 statement: >- Protein S greatly enhances the rate at which activated protein C inactivates factor Va, and has no effect on factor Va by itself. supporting_text: Purified cofactor-protein S caused a large enhancement in the rate of inactivation of Factor Va by activated protein C in the presence of phospholipid. - id: serpina10_zpi label: Protein Z-dependent protease inhibitor inactivation of factor Xa participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SERPINA10 term: id: UniProtKB:Q9UK55 label: Protein Z-dependent protease inhibitor function: preferred_term: serine-type endopeptidase inhibitor activity term: id: GO:0004867 label: serine-type endopeptidase inhibitor activity targets: - preferred_term: coagulation factor Xa term: id: UniProtKB:P00742 label: Coagulation factor X processes: - preferred_term: negative regulation of blood coagulation term: id: GO:0030195 label: negative regulation of blood coagulation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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. evidence: - source_id: PMID:9689066 statement: >- ZPI inhibition of factor Xa is rapid and strictly requires protein Z, calcium and phospholipid. supporting_text: the factor Xa inhibition produced by ZPI is rapid (>95% within 1 min by coagulation assay) and requires the presence of PZ, calcium ions, and cephalin. - id: proz_membrane_cofactor label: Protein Z cofactor in the factor Xa-PZ-ZPI complex participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PROZ term: id: UniProtKB:P22891 label: Vitamin K-dependent protein Z processes: - preferred_term: negative regulation of blood coagulation term: id: GO:0030195 label: negative regulation of blood coagulation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- 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. evidence: - source_id: PMID:9689066 statement: >- The inhibitory reaction proceeds through a factor Xa-protein Z-ZPI complex at the phospholipid surface. supporting_text: The inhibitory process appears to involve the formation of a factor Xa-PZ-ZPI complex at the phospholipid surface. connections: - source: coag_extrinsic_initiation target: coag_prothrombinase connection_type: PROVIDES_INPUT_FOR description: >- The extrinsic tenase makes the first factor Xa, which with factor Va makes the first thrombin. - source: coag_extrinsic_initiation target: coag_intrinsic_amplification connection_type: PROVIDES_INPUT_FOR description: >- The extrinsic tenase also activates factor IX directly, entering the amplification loop without factor XIa (PMID:271951). - source: coag_intrinsic_amplification target: coag_prothrombinase connection_type: PROVIDES_INPUT_FOR description: >- The intrinsic tenase sustains factor Xa production during the propagation phase, after TFPI has quenched the extrinsic tenase. - source: coag_prothrombinase target: coag_thrombin_feedback connection_type: PROVIDES_INPUT_FOR description: Prothrombinase supplies the thrombin that performs the feedback cleavages. - source: coag_thrombin_feedback target: coag_intrinsic_amplification connection_type: POSITIVELY_REGULATES description: >- Thrombin activates factor XI and factor VIII, the entry point and the cofactor of the amplification loop. Contact activation by factor XIIa (modules/kallikrein_kinin_cascade.yaml) is the alternative, upstream route into factor XI activation. - source: coag_thrombin_feedback target: coag_prothrombinase connection_type: POSITIVELY_REGULATES description: >- Thrombin (with factor Xa) activates factor V, the cofactor of its own generating complex — the autocatalytic core of the cascade. - source: coag_prothrombinase target: coag_fibrin_formation connection_type: PROVIDES_INPUT_FOR description: Thrombin is the protease that cleaves fibrinogen. - source: coag_fibrin_formation target: coag_fibrin_crosslinking connection_type: PROVIDES_INPUT_FOR description: >- Fibrin polymer is the substrate of factor XIIIa, and assembly presents the aligned gamma-chain pairs it cross-links. Cross-linked fibrin is in turn the input of modules/fibrinolysis.yaml. - source: coag_anticoagulant_regulation target: coag_extrinsic_initiation connection_type: NEGATIVELY_REGULATES description: TFPI quenches the factor VIIa-tissue factor complex (PMID:3422166). - source: coag_anticoagulant_regulation target: coag_intrinsic_amplification connection_type: NEGATIVELY_REGULATES description: >- Activated protein C destroys factor VIIIa and antithrombin inhibits factor IXa, dismantling the intrinsic tenase. - source: coag_anticoagulant_regulation target: coag_prothrombinase connection_type: NEGATIVELY_REGULATES description: >- Activated protein C cleaves factor Va, antithrombin and ZPI inhibit factor Xa, and antithrombin traps the thrombin produced. - source: coag_prothrombinase target: coag_anticoagulant_regulation connection_type: PROVIDES_INPUT_FOR description: >- Thrombin is also the activator of protein C once it is bound to thrombomodulin, so the cascade switches on its own brake. knowledge_gaps: - gap_statement: >- How much of physiological factor XI activation is done by thrombin, by factor XIIa from the contact system, and by factor XIa autoactivation is still unresolved, and the kinetic measurements that favour thrombin were made in purified systems with non-physiological surfaces such as dextran sulfate. boundary: >- It is firmly established that factor XIa activates factor IX, that factor XIIa and thrombin can both activate factor XI in vitro, and that factor XII deficiency causes no bleeding while factor XI deficiency causes a mild bleeding tendency. status: OPEN gap_kind: - BIOLOGY significance: >- This sets whether factor XI inhibitors act on an amplification loop that is normally thrombin-driven, which is the rationale for antithrombotics that aim to spare haemostasis. provenance: - reference_id: PMID:1652157 supporting_text: Dextran sulfate enhances activation of factor XI by thrombin 2000-fold; part of this effect is due to autoactivation of factor XI by activated factor XI. - gap_statement: >- The quantitative contribution of the protein Z/ZPI system to restraining factor Xa in vivo, relative to antithrombin and TFPI, is unknown, as is the molecular basis of protein Z's cofactor action given that its protease-like domain is catalytically degenerate. boundary: >- It is established that ZPI inhibits factor Xa only in the presence of protein Z, calcium and a phospholipid surface, through a ternary factor Xa-PZ-ZPI complex, and that antithrombin and TFPI inhibit factor Xa independently of protein Z. status: OPEN gap_kind: - BIOLOGY significance: >- Without it the anticoagulant arm of this module cannot be weighted, and protein Z remains a member with no assignable molecular function. provenance: - reference_id: PMID:9689066 supporting_text: Human protein Z (PZ) is a 62,000-Mr, vitamin K-dependent plasma protein whose structure is similar to coagulation factors VII, IX, X, protein C, and protein S, but whose function is not known.