Formation of Fibrin Clot and the Clotting Cascade (Homo sapiens)

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17, 34801821, 22, 5662756, 7813, 15, 28, 3521, 22, 5636, 37, 7616, 31, 39, 61832512, 18, 228316, 31, 39, 6123232, 19, 30, 32, 39...1, 4345, 65, 67, 7720, 33, 51, 5734, 37, 528012, 18, 225917, 3416, 31, 39, 61182748740, 50, 61, 738024184412, 18, 2227, 8421, 22, 564438, 46, 68, 72, 8240, 50, 61, 738338, 46, 68, 72, 8240, 50, 61, 736248276256, 7812, 18, 22278045, 65, 67, 7724441, 432716, 31, 39, 614834, 37, 528424, 5356, 781, 4324, 5327, 842, 19, 30, 32, 39...3, 49, 73, 7440, 50, 61, 7324, 5324, 5324624622, 19, 30, 32, 39...838362278, 13-15, 26...838333, 47, 66, 8720, 33, 51, 5727445, 65, 67, 7748232421, 22, 5640, 50, 61, 7321, 22, 56842413, 15, 28, 35628336, 37, 7621, 22, 5636, 37, 768, 13-15, 26...3, 49, 73, 746233, 47, 66, 8713, 15, 28, 35424, 5317, 34248313, 15, 28, 354813, 15, 28, 3543, 49, 73, 7427, 84272727, 8483448456, 781, 4383434, 37, 528, 13-15, 26...41, 436262cytoplasmFibrinogenkallikreinC1InhKNGC1q binding protein tetramerkallikreinalpha2-macroglobulinTFPIactivated protein Cfactor VIIIaprekallikreinkininogenC1q binding protein tetramerfactor XIIIfactor VIIaTFF7activated kininogenC1q binding protein tetramerZn2+factor XIaGPIbGPIXGPV complexSERPING1prolylcarboxypeptidase dimerfactor XaTFF7aKNG1factor XIII cleaved tetramerfactor VIIIvon Willebrand factor multimerfactor XIIfactor IXavon Willibrand factor multimerfactor XIIaantithrombin IIIheparinfactor VaKNG1factor VKLKB1factor VIIIfactor XIIaC1Inhfibrin multimerC1q binding protein tetramerfactor VIIIafactor IXa11xCbxE-PROS111xCbxE-3D-F9activated protein Cfibrin monomerCa2+Activated thrombin TFPITFF7afactor XaPlatelet Factor 4THBDfactor XIIIafactor X activation peptidePlasma kallikrein10xCbxE-F2kallikreinkininogenC1q binding protein tetramerfactor XGPIb-IX-V complexCa2+FGAVaXa complex SERPINC110xCbxE-F2factor XIGPIb-IX-V complexPROCthrombincleaved antithrombin IIIfactor XIII A chain activation peptide10xCbxE-F7Ca2+protein Cfibrin multimer, crosslinkedHeparinBradykininFGBPalmC-F3thrombincleaved antithrombin IIIheparinsequestered tissue factorthrombinantithrombin IIIheparinfactor V activation peptideactivated thrombinthrombomodulinfactor VIIIa B A3 acidic polypeptideF13BCa2+NH4+factor Vifactor XIAlpha2-macroglobulinfactor IX activation peptidefactor Xa9, 55847070, 849, 558662859, 53, 5542, 5442, 5463626, 5870, 849, 53, 5581756, 58, 608511, 85524


Description

The formation of a fibrin clot at the site of an injury to the wall of a normal blood vessel is an essential part of the process to stop blood loss after vascular injury. The reactions that lead to fibrin clot formation are commonly described as a cascade, in which the product of each step is an enzyme or cofactor needed for following reactions to proceed efficiently. The entire clotting cascade can be divided into three portions, the extrinsic pathway, the intrinsic pathway, and the common pathway. The extrinsic pathway begins with the release of tissue factor at the site of vascular injury and leads to the activation of factor X. The intrinsic pathway provides an alternative mechanism for activation of factor X, starting from the activation of factor XII. The common pathway consists of the steps linking the activation of factor X to the formation of a multimeric, cross-linked fibrin clot. Each of these pathways includes not only a cascade of events that generate the catalytic activities needed for clot formation, but also numerous positive and negative regulatory events. <a href=http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=140877>View original pathway at Reactome</a>

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  126. Church FC, Noyes CM, Griffith MJ.; ''Inhibition of chymotrypsin by heparin cofactor II.''; PubMed Europe PMC Scholia
  127. Lewis SD, Janus TJ, Lorand L, Shafer JA.; ''Regulation of formation of factor XIIIa by its fibrin substrates.''; PubMed Europe PMC Scholia
  128. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J.; ''Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors.''; PubMed Europe PMC Scholia
  129. Pan S, Iannotti MJ, Sifers RN.; ''Analysis of serpin secretion, misfolding, and surveillance in the endoplasmic reticulum.''; PubMed Europe PMC Scholia
  130. Nemerson Y.; ''Tissue factor and hemostasis.''; PubMed Europe PMC Scholia
  131. Yegneswaran S, Smirnov MD, Safa O, Esmon NL, Esmon CT, Johnson AE.; ''Relocating the active site of activated protein C eliminates the need for its protein S cofactor. A fluorescence resonance energy transfer study.''; PubMed Europe PMC Scholia
  132. Pipe SW, Eickhorst AN, McKinley SH, Saenko EL, Kaufman RJ.; ''Mild hemophilia A caused by increased rate of factor VIII A2 subunit dissociation: evidence for nonproteolytic inactivation of factor VIIIa in vivo.''; PubMed Europe PMC Scholia
  133. Rosing J, Hoekema L, Nicolaes GA, Thomassen MC, Hemker HC, Varadi K, Schwarz HP, Tans G.; ''Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C.''; PubMed Europe PMC Scholia
  134. Di Scipio RG, Hermodson MA, Davie EW.; ''Activation of human factor X (Stuart factor) by a protease from Russell's viper venom.''; PubMed Europe PMC Scholia
  135. Hoeben RC, Fallaux FJ, Cramer SJ, van den Wollenberg DJ, van Ormondt H, Briët E, van der Eb AJ.; ''Expression of the blood-clotting factor-VIII cDNA is repressed by a transcriptional silencer located in its coding region.''; PubMed Europe PMC Scholia
  136. Gilbert GE, Furie BC, Furie B.; ''Binding of human factor VIII to phospholipid vesicles.''; PubMed Europe PMC Scholia
  137. Schmaier AH.; ''The physiologic basis of assembly and activation of the plasma kallikrein/kinin system.''; PubMed Europe PMC Scholia
  138. Kellermann J, Lottspeich F, Henschen A, Müller-Esterl W.; ''Completion of the primary structure of human high-molecular-mass kininogen. The amino acid sequence of the entire heavy chain and evidence for its evolution by gene triplication.''; PubMed Europe PMC Scholia
  139. Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N.; ''In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate.''; PubMed Europe PMC Scholia
  140. Butkowski RJ, Elion J, Downing MR, Mann KG.; ''Primary structure of human prethrombin 2 and alpha-thrombin.''; PubMed Europe PMC Scholia
  141. Shariat-Madar Z, Mahdi F, Schmaier AH.; ''Recombinant prolylcarboxypeptidase activates plasma prekallikrein.''; PubMed Europe PMC Scholia
  142. Greengard JS, Heeb MJ, Ersdal E, Walsh PN, Griffin JH.; ''Binding of coagulation factor XI to washed human platelets.''; PubMed Europe PMC Scholia
  143. Holmer E, Söderberg K, Bergqvist D, Lindahl U.; ''Heparin and its low molecular weight derivatives: anticoagulant and antithrombotic properties.''; PubMed Europe PMC Scholia
  144. Kurosawa S, Esmon CT, Stearns-Kurosawa DJ.; ''The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18.''; PubMed Europe PMC Scholia
  145. Kurachi K, Kurachi S, Furukawa M, Yao SN.; ''Biology of factor IX.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
123618view08:20, 7 August 2022EgonwModified title
114744view16:23, 25 January 2021ReactomeTeamReactome version 75
113188view11:25, 2 November 2020ReactomeTeamReactome version 74
112416view15:35, 9 October 2020ReactomeTeamReactome version 73
101320view11:21, 1 November 2018ReactomeTeamreactome version 66
100857view20:53, 31 October 2018ReactomeTeamreactome version 65
100398view19:27, 31 October 2018ReactomeTeamreactome version 64
99946view16:11, 31 October 2018ReactomeTeamreactome version 63
99502view14:44, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94025view13:52, 16 August 2017ReactomeTeamreactome version 61
93645view11:29, 9 August 2017ReactomeTeamreactome version 61
87449view13:55, 22 July 2016MkutmonOntology Term : 'coagulation cascade pathway' added !
86761view09:25, 11 July 2016ReactomeTeamreactome version 56
83143view10:09, 18 November 2015ReactomeTeamVersion54
81490view13:01, 21 August 2015ReactomeTeamVersion53
76965view08:24, 17 July 2014ReactomeTeamFixed remaining interactions
76670view12:03, 16 July 2014ReactomeTeamFixed remaining interactions
75999view10:05, 11 June 2014ReactomeTeamRe-fixing comment source
75702view11:04, 10 June 2014ReactomeTeamReactome 48 Update
75538view19:27, 9 June 2014MaintBotchanged description source
75512view12:25, 5 June 2014AnweshaUpdated in Reactome48
75058view13:56, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74702view08:46, 30 April 2014ReactomeTeamReactome46
73650view00:25, 12 February 2014AriuttaRemoved GroupRef="group_comp_1316" because there is no Group with GroupId="group_comp_1316"
73634view20:28, 10 February 2014KhanspersReverted to version '20:24, 8 February 2014' by Khanspers
73633view20:24, 10 February 2014Khanspersremoved cell shape
73632view20:22, 10 February 2014Khanspersremoved all groups to possibly resolve crash
73624view20:24, 8 February 2014MaintBotTrying out new gpml conversion to resolve crash of new pvjs viewer
69011view17:46, 8 July 2013MaintBotUpdated to 2013 gpml schema
42041view21:52, 4 March 2011MaintBotAutomatic update
39844view05:52, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
10xCbxE-F2ProteinP00734 (Uniprot-SwissProt)
10xCbxE-F7ProteinP08709 (Uniprot-SwissProt)
11xCbxE-3D-F9ProteinP00740 (Uniprot-SwissProt)
11xCbxE-PROS1ProteinP07225 (Uniprot-SwissProt)
Activated thrombin ComplexREACT_3298 (Reactome)
Alpha2-macroglobulinComplexREACT_3449 (Reactome)
BradykininProteinP01042 (Uniprot-SwissProt)
C1q binding protein tetramerComplexREACT_2937 (Reactome)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
F13BProteinP05160 (Uniprot-SwissProt)
FGAProteinP02671 (Uniprot-SwissProt)
FGBProteinP02675 (Uniprot-SwissProt)
FibrinogenComplexREACT_4095 (Reactome)
  • Fibrinogen is a hexamer, containing two fibrinogen alpha chains, two fibrinogen beta chains, and two fibrinogen gamma chains, held together by disulfide bonds.
  • Fibrinogen is a hexamer, containing two fibrinogen alpha chains, two fibrinogen beta chains, and two fibrinogen gamma chains, held together by disulfide bonds.
GPIb-IX-V complexComplexREACT_3007 (Reactome)
HeparinREACT_4737 (Reactome)
KLKB1ProteinP03952 (Uniprot-SwissProt)
KNG C1q binding protein tetramerComplexREACT_4804 (Reactome)
KNG1ProteinP01042 (Uniprot-SwissProt)
NH4+MetaboliteCHEBI:28938 (ChEBI)
PROCProteinP04070 (Uniprot-SwissProt)
PalmC-F3ProteinP13726 (Uniprot-SwissProt)
Plasma kallikreinComplexREACT_4124 (Reactome)
Platelet Factor 4REACT_12205 (Reactome)
SERPINC1ProteinP01008 (Uniprot-SwissProt)
SERPING1ProteinP05155 (Uniprot-SwissProt)
TF F7ComplexREACT_4908 (Reactome)
TF F7aComplexREACT_4532 (Reactome)
TFPI

TF F7a

factor Xa		ComplexREACT_2685 (Reactome)
TFPIProteinP10646 (Uniprot-SwissProt)
THBDProteinP07204 (Uniprot-SwissProt)
Va Xa complex ComplexREACT_5441 (Reactome)
Zn2+MetaboliteCHEBI:29105 (ChEBI)
activated kininogen C1q binding protein tetramerComplexREACT_3121 (Reactome)
activated protein CComplexREACT_2599 (Reactome)
activated protein CComplexREACT_5044 (Reactome)
activated thrombin thrombomodulinComplexREACT_5904 (Reactome)
antithrombin III heparinComplexREACT_2653 (Reactome)
factor IX activation peptideProteinP00740 (Uniprot-SwissProt)
factor IXaComplexREACT_3075 (Reactome)
factor V activation peptideProteinP12259 (Uniprot-SwissProt)
factor VIII von Willebrand factor multimerComplexREACT_3248 (Reactome)
factor VIIIComplexREACT_4493 (Reactome)
factor VIIIa factor IXaComplexREACT_3217 (Reactome)
factor VIIIa B A3 acidic polypeptideProteinP00451 (Uniprot-SwissProt)
factor VIIIaComplexREACT_4190 (Reactome)
factor VIIaComplexREACT_2419 (Reactome)
factor VProteinP12259 (Uniprot-SwissProt)
factor VaComplexREACT_2497 (Reactome)
factor ViComplexREACT_4020 (Reactome)
factor X activation peptideProteinP00742 (Uniprot-SwissProt)
factor XI GPIb-IX-V complexComplexREACT_5726 (Reactome)
factor XIII A chain activation peptideProteinP00488 (Uniprot-SwissProt)
factor XIII cleaved tetramerComplexREACT_2648 (Reactome)
factor XIIIComplexREACT_4285 (Reactome)
factor XIIIaComplexREACT_4387 (Reactome)
factor XIIProteinP00748 (Uniprot-SwissProt)
factor XIIa C1InhComplexREACT_2283 (Reactome)
factor XIIaComplexREACT_4236 (Reactome)
factor XIComplexREACT_4915 (Reactome)
factor XIa

GPIb GPIX

GPV complex		ComplexREACT_4765 (Reactome)
factor XComplexREACT_3749 (Reactome)
factor XaComplexREACT_3099 (Reactome)
factor XaComplexREACT_5349 (Reactome)
fibrin monomerComplexREACT_5594 (Reactome)
  • Fibrin is a hexamer of two fibrinogen alpha chains, two fibrinogen beta chains, and two fibrinogen gamma chains, held together by disulfide bonds. It is formed in vivo by the thrombin-catalyzed removal of amino terminal fibinopeptides from the A alpha and B beta chains of fibrinogen. This fibrin hexamer ("fibrin monomer") is the subunit that multimerizes to form a fibrin clot ("fibrin multimer").
  • Fibrin is a hexamer of two fibrinogen alpha chains, two fibrinogen beta chains, and two fibrinogen gamma chains, held together by disulfide bonds. It is formed in vivo by the thrombin-catalyzed removal of amino terminal fibinopeptides from the A alpha and B beta chains of fibrinogen. This fibrin hexamer ("fibrin monomer") is the subunit that multimerizes to form a fibrin clot ("fibrin multimer").
fibrin multimer, crosslinkedREACT_2721 (Reactome)
fibrin multimerComplexREACT_4444 (Reactome)
  • The fibrin "monomers" formed by the action of thrombin on fibrinogen associate spontaneously into multimers. This association can follow several distinct pathways and may be able to form several types of higher-order structures. All of these possibilities are represented in Reactome as a fibrin trimer.
  • The fibrin "monomers" formed by the action of thrombin on fibrinogen associate spontaneously into multimers. This association can follow several distinct pathways and may be able to form several types of higher-order structures. All of these possibilities are represented in Reactome as a fibrin trimer.
kallikrein C1InhComplexREACT_5874 (Reactome)
kallikrein alpha2-macroglobulinComplexREACT_4115 (Reactome)
kallikrein

kininogen

C1q binding protein tetramer		ComplexREACT_4714 (Reactome)
prekallikrein

kininogen

C1q binding protein tetramer		ComplexREACT_3461 (Reactome)
prolylcarboxypeptidase dimerComplexREACT_5699 (Reactome)
protein CComplexREACT_4912 (Reactome)
sequestered tissue factorProteinP13726 (Uniprot-SwissProt)
thrombin

antithrombin III

heparin		ComplexREACT_2423 (Reactome)
thrombin

cleaved antithrombin III

heparin		ComplexREACT_2621 (Reactome)
thrombin cleaved antithrombin IIIComplexREACT_4175 (Reactome)
von Willibrand factor multimerComplexREACT_5706 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
10xCbxE-F2ArrowREACT_1097 (Reactome)
  • Membrane-bound factor Xa catalyzes the activation of small amounts of thrombin. The amino terminal portion of prothrombin is released as an activation peptide, which can be cleaved further by activated thrombin. Neither the full-length activation peptide nor its cleavage products have known functions.
  • Membrane-bound factor Xa catalyzes the activation of small amounts of thrombin. The amino terminal portion of prothrombin is released as an activation peptide, which can be cleaved further by activated thrombin. Neither the full-length activation peptide nor its cleavage products have known functions.
10xCbxE-F2ArrowREACT_1446 (Reactome)
  • The membrane-bound Va:Xa (prothrombinase) complex rapidly activates large amounts of thrombin.
  • The membrane-bound Va:Xa (prothrombinase) complex rapidly activates large amounts of thrombin.
10xCbxE-F2REACT_1097 (Reactome)
  • Membrane-bound factor Xa catalyzes the activation of small amounts of thrombin. The amino terminal portion of prothrombin is released as an activation peptide, which can be cleaved further by activated thrombin. Neither the full-length activation peptide nor its cleavage products have known functions.
  • Membrane-bound factor Xa catalyzes the activation of small amounts of thrombin. The amino terminal portion of prothrombin is released as an activation peptide, which can be cleaved further by activated thrombin. Neither the full-length activation peptide nor its cleavage products have known functions.
10xCbxE-F2REACT_1446 (Reactome)
  • The membrane-bound Va:Xa (prothrombinase) complex rapidly activates large amounts of thrombin.
  • The membrane-bound Va:Xa (prothrombinase) complex rapidly activates large amounts of thrombin.
10xCbxE-F7REACT_1669 (Reactome)
  • Tissue factor exposed at the endothelial cell surface forms a complex with factor VII from plasma.
  • Tissue factor exposed at the endothelial cell surface forms a complex with factor VII from plasma.
10xCbxE-F7factor VIIaArrowREACT_9 (Reactome)
  • Factor Xa catalyzes the activation of factor VII from plasma.
  • Factor Xa catalyzes the activation of factor VII from plasma.
11xCbxE-3D-F9REACT_158 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface, catalyzes the formation of activated factor IX with high efficiency. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface, catalyzes the formation of activated factor IX with high efficiency. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
11xCbxE-3D-F9REACT_2073 (Reactome)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
11xCbxE-PROS1ArrowREACT_1071 (Reactome)
  • Activated protein C cleaves peptide bonds in activated factor V (factor Va), converting it to an inactive form (factor Vi). The exact site(s) of cleavage are unknown. Protein S, on the endothelial cell surface, positively regulates this reaction. Although the mechanism of this regulation is unclear, the regulation is physiologically important, as people with reduced amounts of protein S, like people with reduced amounts of protein C, are susceptible to thromboembolism.
  • Activated protein C cleaves peptide bonds in activated factor V (factor Va), converting it to an inactive form (factor Vi). The exact site(s) of cleavage are unknown. Protein S, on the endothelial cell surface, positively regulates this reaction. Although the mechanism of this regulation is unclear, the regulation is physiologically important, as people with reduced amounts of protein S, like people with reduced amounts of protein C, are susceptible to thromboembolism.
Activated thrombin ArrowREACT_1097 (Reactome)
  • Membrane-bound factor Xa catalyzes the activation of small amounts of thrombin. The amino terminal portion of prothrombin is released as an activation peptide, which can be cleaved further by activated thrombin. Neither the full-length activation peptide nor its cleavage products have known functions.
  • Membrane-bound factor Xa catalyzes the activation of small amounts of thrombin. The amino terminal portion of prothrombin is released as an activation peptide, which can be cleaved further by activated thrombin. Neither the full-length activation peptide nor its cleavage products have known functions.
Activated thrombin ArrowREACT_1446 (Reactome)
  • The membrane-bound Va:Xa (prothrombinase) complex rapidly activates large amounts of thrombin.
  • The membrane-bound Va:Xa (prothrombinase) complex rapidly activates large amounts of thrombin.
Activated thrombin REACT_1822 (Reactome)
  • Activated thrombin binds to the antithrombin III:heparin complex on the cell surface.
  • Activated thrombin binds to the antithrombin III:heparin complex on the cell surface.
Activated thrombin REACT_1834 (Reactome)
  • Activated thrombin (factor IIa) binds to thrombomodulin at the external face of the plasma membrane, forming a thrombin:thrombomodulin complex. In this complexed form, the activity of thrombin towards protein C is greatly increased, and as thrombomodulin is particularly abundant on the surfaces of endothelial cells, this association plays a major role in restricting clot formation.
  • Activated thrombin (factor IIa) binds to thrombomodulin at the external face of the plasma membrane, forming a thrombin:thrombomodulin complex. In this complexed form, the activity of thrombin towards protein C is greatly increased, and as thrombomodulin is particularly abundant on the surfaces of endothelial cells, this association plays a major role in restricting clot formation.
Activated thrombin mim-catalysisREACT_1536 (Reactome)
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
Activated thrombin mim-catalysisREACT_1581 (Reactome)
  • Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). In the body, this reaction occurs on the surfaces of activated platelets (Baglia et al. 2002). Small quantities of factor XI can be activated in a reaction catalyzed by factor XIIa, to initiate formation of a fibrin clot. However, the efficient activation of larger quantities of factor XI, needed to propagate the blood clotting process, appears to be mediated by thrombin (Baglia and Walsh 2000; Gailani and Broze 1993; Naito and Fujikawa 1991; Oliver et al. 1999; Monroe et al. 2002).
  • Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). In the body, this reaction occurs on the surfaces of activated platelets (Baglia et al. 2002). Small quantities of factor XI can be activated in a reaction catalyzed by factor XIIa, to initiate formation of a fibrin clot. However, the efficient activation of larger quantities of factor XI, needed to propagate the blood clotting process, appears to be mediated by thrombin (Baglia and Walsh 2000; Gailani and Broze 1993; Naito and Fujikawa 1991; Oliver et al. 1999; Monroe et al. 2002).
Activated thrombin mim-catalysisREACT_214 (Reactome)
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
Activated thrombin mim-catalysisREACT_217 (Reactome)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
Activated thrombin mim-catalysisREACT_708 (Reactome)
  • Activated thrombin (factor IIa) catalyzes the conversion of factor V to factor Va (activated factor V). The activation peptide released in this reaction has no known function.
  • Activated thrombin (factor IIa) catalyzes the conversion of factor V to factor Va (activated factor V). The activation peptide released in this reaction has no known function.
Alpha2-macroglobulinREACT_25 (Reactome)
  • Activated kallikrein binds to alpha2-macroglobulin (Sottrup-Jensen et al. 1984), forming a stable and enzymatically inactive complex. Under normal conditions in vivo, this reaction appears to be responsible for the inactivation of about 1/6 of activated kallikrein (with C1Inh responsible for the inactivation of about 5/6) (Harpel et al. 1985).
  • Activated kallikrein binds to alpha2-macroglobulin (Sottrup-Jensen et al. 1984), forming a stable and enzymatically inactive complex. Under normal conditions in vivo, this reaction appears to be responsible for the inactivation of about 1/6 of activated kallikrein (with C1Inh responsible for the inactivation of about 5/6) (Harpel et al. 1985).
BradykininArrowREACT_2004 (Reactome)
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
C1q binding protein tetramerREACT_2239 (Reactome)
  • Kininogen (high molecular weight kininogen; HK) associates with C1q binding protein on the cell surface in a reaction dependent on Zn++ (Joseph et al. 1996). In the body, the Zn++ needed to drive this reaction may be provided locally by Zn++ release from activated platelets (Mahdi et al. 2002). The C1q binding protein is inferred to form tetramers based on the properties of purified recombinant protein in vitro (Ghebrehiwet et al. 1994); the stoichiometry of the cell surface complex has not been determined directly.
  • Kininogen (high molecular weight kininogen; HK) associates with C1q binding protein on the cell surface in a reaction dependent on Zn++ (Joseph et al. 1996). In the body, the Zn++ needed to drive this reaction may be provided locally by Zn++ release from activated platelets (Mahdi et al. 2002). The C1q binding protein is inferred to form tetramers based on the properties of purified recombinant protein in vitro (Ghebrehiwet et al. 1994); the stoichiometry of the cell surface complex has not been determined directly.
Ca2+ArrowREACT_112 (Reactome)
  • The activated forms of factors VIII and IX associate on a cell surface to form a complex that very efficiently catalyzes the activation of factor X, the so-called "intrinsic tenase complex". In vitro, negatively charged phospholipids can provide an appropriate surface. In the body, the surface is provided by the plasma membranes of activated platelets (Gilbert and Arena 1996).
  • The activated forms of factors VIII and IX associate on a cell surface to form a complex that very efficiently catalyzes the activation of factor X, the so-called "intrinsic tenase complex". In vitro, negatively charged phospholipids can provide an appropriate surface. In the body, the surface is provided by the plasma membranes of activated platelets (Gilbert and Arena 1996).
Ca2+ArrowREACT_2073 (Reactome)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
Ca2+REACT_1314 (Reactome)
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
Ca2+REACT_1668 (Reactome)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
Ca2+REACT_245 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
F13BArrowREACT_1314 (Reactome)
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
FGAArrowREACT_214 (Reactome)
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
FGBArrowREACT_214 (Reactome)
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
FibrinogenREACT_214 (Reactome)
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
GPIb-IX-V complexREACT_177 (Reactome)
  • Plasma factor XI binds to the platelet glycoprotein Ib:IX:V complex (Baglia et al. 2002; Greengard et al. 1986). In the body, this reaction occurs specifically on the surfaces of activated platelets, but not on endothelial cells (Baird and Walsh 2002). The stoichiometry of the platelet glycoprotein Ib:IX:V complex has not been established directly, but is inferred from the relative abundances of its components in platelet membranes (Modderman et al. 1992; Shrimpton et al. 2002).
  • Plasma factor XI binds to the platelet glycoprotein Ib:IX:V complex (Baglia et al. 2002; Greengard et al. 1986). In the body, this reaction occurs specifically on the surfaces of activated platelets, but not on endothelial cells (Baird and Walsh 2002). The stoichiometry of the platelet glycoprotein Ib:IX:V complex has not been established directly, but is inferred from the relative abundances of its components in platelet membranes (Modderman et al. 1992; Shrimpton et al. 2002).
HeparinArrowREACT_1283 (Reactome)
  • The same conformational change that traps thrombin in its complex with cleaved antithrombin III also decreases the affinity of the latter for heparin, and the complex of cleaved antithrombin III and thrombin dissociates from the cell-bound heparin molecule.
  • The same conformational change that traps thrombin in its complex with cleaved antithrombin III also decreases the affinity of the latter for heparin, and the complex of cleaved antithrombin III and thrombin dissociates from the cell-bound heparin molecule.
HeparinREACT_102 (Reactome)
  • Antithrombin III binds to membrane-associated heparin, e.g., on the surface of a normal endothelial cell. This binding event increases the affinity of antithrombin III for thrombin approximately 1000-fold.
  • Antithrombin III binds to membrane-associated heparin, e.g., on the surface of a normal endothelial cell. This binding event increases the affinity of antithrombin III for thrombin approximately 1000-fold.
KLKB1REACT_1335 (Reactome)
  • Prekallikrein (PK) associates specifically with kininogen (HK) on cell surfaces. In vivo, this reaction may occur primarily on the surfaces of endothelial cells in response to platelet activation (Lin et al. 1997; Motta et al. 1998; Mahdi et al. 2003).
  • Prekallikrein (PK) associates specifically with kininogen (HK) on cell surfaces. In vivo, this reaction may occur primarily on the surfaces of endothelial cells in response to platelet activation (Lin et al. 1997; Motta et al. 1998; Mahdi et al. 2003).
KNG C1q binding protein tetramerArrowREACT_2239 (Reactome)
  • Kininogen (high molecular weight kininogen; HK) associates with C1q binding protein on the cell surface in a reaction dependent on Zn++ (Joseph et al. 1996). In the body, the Zn++ needed to drive this reaction may be provided locally by Zn++ release from activated platelets (Mahdi et al. 2002). The C1q binding protein is inferred to form tetramers based on the properties of purified recombinant protein in vitro (Ghebrehiwet et al. 1994); the stoichiometry of the cell surface complex has not been determined directly.
  • Kininogen (high molecular weight kininogen; HK) associates with C1q binding protein on the cell surface in a reaction dependent on Zn++ (Joseph et al. 1996). In the body, the Zn++ needed to drive this reaction may be provided locally by Zn++ release from activated platelets (Mahdi et al. 2002). The C1q binding protein is inferred to form tetramers based on the properties of purified recombinant protein in vitro (Ghebrehiwet et al. 1994); the stoichiometry of the cell surface complex has not been determined directly.
KNG C1q binding protein tetramerREACT_1335 (Reactome)
  • Prekallikrein (PK) associates specifically with kininogen (HK) on cell surfaces. In vivo, this reaction may occur primarily on the surfaces of endothelial cells in response to platelet activation (Lin et al. 1997; Motta et al. 1998; Mahdi et al. 2003).
  • Prekallikrein (PK) associates specifically with kininogen (HK) on cell surfaces. In vivo, this reaction may occur primarily on the surfaces of endothelial cells in response to platelet activation (Lin et al. 1997; Motta et al. 1998; Mahdi et al. 2003).
KNG1ArrowREACT_1455 (Reactome)
  • Cleavage of a single peptide bond converts factor XII to activated factor XII (factor XIIa) (Fujikawa and McMullen 1983; McMullen and Fujikawa 1985). Identification of the catalytic activity or activities responsible for this cleavage has not been straightforward. Studies in vitro have demonstrated the autoactivation of factor XII as well as activation by kallikrein. Both reactions require the presence of negatively charged surfaces and are accelerated in the presence of kininogen (high molecular weight kininogen, HK) (Griffin and Cochrane 1976; Meier et al. 1977; Silverberg et al. 1980). Recent work suggests that factor XII activation in vivo may occur primarily on endothelial cell surfaces and that, as in vitro, association with kininogen may accelerate the reaction (Mahdi et al. 2002; Schmaier 2004), although alternative pathways and alternative mechanisms for associating factor XII with the cell surface have not been excluded (Joseph et al. 2001).
  • Cleavage of a single peptide bond converts factor XII to activated factor XII (factor XIIa) (Fujikawa and McMullen 1983; McMullen and Fujikawa 1985). Identification of the catalytic activity or activities responsible for this cleavage has not been straightforward. Studies in vitro have demonstrated the autoactivation of factor XII as well as activation by kallikrein. Both reactions require the presence of negatively charged surfaces and are accelerated in the presence of kininogen (high molecular weight kininogen, HK) (Griffin and Cochrane 1976; Meier et al. 1977; Silverberg et al. 1980). Recent work suggests that factor XII activation in vivo may occur primarily on endothelial cell surfaces and that, as in vitro, association with kininogen may accelerate the reaction (Mahdi et al. 2002; Schmaier 2004), although alternative pathways and alternative mechanisms for associating factor XII with the cell surface have not been excluded (Joseph et al. 2001).
KNG1REACT_2239 (Reactome)
  • Kininogen (high molecular weight kininogen; HK) associates with C1q binding protein on the cell surface in a reaction dependent on Zn++ (Joseph et al. 1996). In the body, the Zn++ needed to drive this reaction may be provided locally by Zn++ release from activated platelets (Mahdi et al. 2002). The C1q binding protein is inferred to form tetramers based on the properties of purified recombinant protein in vitro (Ghebrehiwet et al. 1994); the stoichiometry of the cell surface complex has not been determined directly.
  • Kininogen (high molecular weight kininogen; HK) associates with C1q binding protein on the cell surface in a reaction dependent on Zn++ (Joseph et al. 1996). In the body, the Zn++ needed to drive this reaction may be provided locally by Zn++ release from activated platelets (Mahdi et al. 2002). The C1q binding protein is inferred to form tetramers based on the properties of purified recombinant protein in vitro (Ghebrehiwet et al. 1994); the stoichiometry of the cell surface complex has not been determined directly.
NH4+ArrowREACT_1852 (Reactome)
  • Fibrin multimers are stabilized by the formation of multiple covalent crosslinks between the side chains of specific lysine and glutamine residues in fibrinogen alpha and gamma chains, catalyzed by factor XIIIa.
  • Fibrin multimers are stabilized by the formation of multiple covalent crosslinks between the side chains of specific lysine and glutamine residues in fibrinogen alpha and gamma chains, catalyzed by factor XIIIa.
PROCArrowREACT_374 (Reactome)
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
PalmC-F3REACT_137 (Reactome)
  • Tissue factor exposed at the endothelial cell surface forms a complex with F7a (activated factor VII) from the plasma
  • Tissue factor exposed at the endothelial cell surface forms a complex with F7a (activated factor VII) from the plasma
PalmC-F3REACT_1669 (Reactome)
  • Tissue factor exposed at the endothelial cell surface forms a complex with factor VII from plasma.
  • Tissue factor exposed at the endothelial cell surface forms a complex with factor VII from plasma.
Plasma kallikreinArrowREACT_2004 (Reactome)
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
Plasma kallikreinREACT_1486 (Reactome)
  • Activated kallikrein binds to C1Inh (plasma protease C1 inhibitor) (Bock et al. 1986), forming a stable and enzymatically inactive complex. This reaction appears to be the major means by which kallikrein is inactivated (kallikrein can also be inactivated by binding to alpha2-macroglobulin) (Harpel et al. 1985; Ratnoff et al. 1969).
  • Activated kallikrein binds to C1Inh (plasma protease C1 inhibitor) (Bock et al. 1986), forming a stable and enzymatically inactive complex. This reaction appears to be the major means by which kallikrein is inactivated (kallikrein can also be inactivated by binding to alpha2-macroglobulin) (Harpel et al. 1985; Ratnoff et al. 1969).
Plasma kallikreinREACT_25 (Reactome)
  • Activated kallikrein binds to alpha2-macroglobulin (Sottrup-Jensen et al. 1984), forming a stable and enzymatically inactive complex. Under normal conditions in vivo, this reaction appears to be responsible for the inactivation of about 1/6 of activated kallikrein (with C1Inh responsible for the inactivation of about 5/6) (Harpel et al. 1985).
  • Activated kallikrein binds to alpha2-macroglobulin (Sottrup-Jensen et al. 1984), forming a stable and enzymatically inactive complex. Under normal conditions in vivo, this reaction appears to be responsible for the inactivation of about 1/6 of activated kallikrein (with C1Inh responsible for the inactivation of about 5/6) (Harpel et al. 1985).
Platelet Factor 4ArrowREACT_374 (Reactome)
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
REACT_1314 (Reactome)
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
REACT_1668 (Reactome)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
REACT_245 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
SERPINC1REACT_102 (Reactome)
  • Antithrombin III binds to membrane-associated heparin, e.g., on the surface of a normal endothelial cell. This binding event increases the affinity of antithrombin III for thrombin approximately 1000-fold.
  • Antithrombin III binds to membrane-associated heparin, e.g., on the surface of a normal endothelial cell. This binding event increases the affinity of antithrombin III for thrombin approximately 1000-fold.
SERPING1REACT_1486 (Reactome)
  • Activated kallikrein binds to C1Inh (plasma protease C1 inhibitor) (Bock et al. 1986), forming a stable and enzymatically inactive complex. This reaction appears to be the major means by which kallikrein is inactivated (kallikrein can also be inactivated by binding to alpha2-macroglobulin) (Harpel et al. 1985; Ratnoff et al. 1969).
  • Activated kallikrein binds to C1Inh (plasma protease C1 inhibitor) (Bock et al. 1986), forming a stable and enzymatically inactive complex. This reaction appears to be the major means by which kallikrein is inactivated (kallikrein can also be inactivated by binding to alpha2-macroglobulin) (Harpel et al. 1985; Ratnoff et al. 1969).
SERPING1REACT_825 (Reactome)
  • Activated factor XII (factor XIIa) binds to C1Inh (C1 inhibitor - Bock et al. 1986) to form a stable, inactive complex (Schneider et al. 1973). While several protease inhibitors can form stable complexes with XIIa in vitro, only C1Inh does so to a significant extent under normal conditions in vivo (Pixley et al. 1985).
  • Activated factor XII (factor XIIa) binds to C1Inh (C1 inhibitor - Bock et al. 1986) to form a stable, inactive complex (Schneider et al. 1973). While several protease inhibitors can form stable complexes with XIIa in vitro, only C1Inh does so to a significant extent under normal conditions in vivo (Pixley et al. 1985).
TF F7ArrowREACT_1669 (Reactome)
  • Tissue factor exposed at the endothelial cell surface forms a complex with factor VII from plasma.
  • Tissue factor exposed at the endothelial cell surface forms a complex with factor VII from plasma.
TF F7aArrowREACT_137 (Reactome)
  • Tissue factor exposed at the endothelial cell surface forms a complex with F7a (activated factor VII) from the plasma
  • Tissue factor exposed at the endothelial cell surface forms a complex with F7a (activated factor VII) from the plasma
TF F7aREACT_654 (Reactome)
  • TFPI binds to the factor VIIa:TF complex and to factor Xa at the endothelial surface, forming a stable heterotetrameric complex in which factor VIIa is catalytically inactive.
  • TFPI binds to the factor VIIa:TF complex and to factor Xa at the endothelial surface, forming a stable heterotetrameric complex in which factor VIIa is catalytically inactive.
TF F7amim-catalysisREACT_158 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface, catalyzes the formation of activated factor IX with high efficiency. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface, catalyzes the formation of activated factor IX with high efficiency. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
TF F7amim-catalysisREACT_245 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
TF F7mim-catalysisREACT_493 (Reactome)
  • Factor VII, bound to tissue factor at the endothelial cell surface, catalyzes the activation of factor X from plasma with moderate efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VII, bound to tissue factor at the endothelial cell surface, catalyzes the activation of factor X from plasma with moderate efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
TFPI

TF F7a

factor Xa		ArrowREACT_654 (Reactome)
  • TFPI binds to the factor VIIa:TF complex and to factor Xa at the endothelial surface, forming a stable heterotetrameric complex in which factor VIIa is catalytically inactive.
  • TFPI binds to the factor VIIa:TF complex and to factor Xa at the endothelial surface, forming a stable heterotetrameric complex in which factor VIIa is catalytically inactive.
TFPIREACT_654 (Reactome)
  • TFPI binds to the factor VIIa:TF complex and to factor Xa at the endothelial surface, forming a stable heterotetrameric complex in which factor VIIa is catalytically inactive.
  • TFPI binds to the factor VIIa:TF complex and to factor Xa at the endothelial surface, forming a stable heterotetrameric complex in which factor VIIa is catalytically inactive.
THBDREACT_1834 (Reactome)
  • Activated thrombin (factor IIa) binds to thrombomodulin at the external face of the plasma membrane, forming a thrombin:thrombomodulin complex. In this complexed form, the activity of thrombin towards protein C is greatly increased, and as thrombomodulin is particularly abundant on the surfaces of endothelial cells, this association plays a major role in restricting clot formation.
  • Activated thrombin (factor IIa) binds to thrombomodulin at the external face of the plasma membrane, forming a thrombin:thrombomodulin complex. In this complexed form, the activity of thrombin towards protein C is greatly increased, and as thrombomodulin is particularly abundant on the surfaces of endothelial cells, this association plays a major role in restricting clot formation.
Va Xa complex ArrowREACT_675 (Reactome)
  • Factors Va and Xa associate on a membrane surface to form a complex in which the activity of factor Xa on prothrombin is greatly increased (Mann et al. 1988). The presence of negatively charged phospholipid in the membrane greatly facilitates this process, a feature that may contribute to its localization, as such phospholipids are normally on the cytosolic face of the plasma membrane (Devaux 1992), but could be exposed to the extracellular space following platelet activation or mechanical injury to endothelial cells.
  • Factors Va and Xa associate on a membrane surface to form a complex in which the activity of factor Xa on prothrombin is greatly increased (Mann et al. 1988). The presence of negatively charged phospholipid in the membrane greatly facilitates this process, a feature that may contribute to its localization, as such phospholipids are normally on the cytosolic face of the plasma membrane (Devaux 1992), but could be exposed to the extracellular space following platelet activation or mechanical injury to endothelial cells.
Va Xa complex mim-catalysisREACT_1446 (Reactome)
  • The membrane-bound Va:Xa (prothrombinase) complex rapidly activates large amounts of thrombin.
  • The membrane-bound Va:Xa (prothrombinase) complex rapidly activates large amounts of thrombin.
Zn2+ArrowREACT_2239 (Reactome)
  • Kininogen (high molecular weight kininogen; HK) associates with C1q binding protein on the cell surface in a reaction dependent on Zn++ (Joseph et al. 1996). In the body, the Zn++ needed to drive this reaction may be provided locally by Zn++ release from activated platelets (Mahdi et al. 2002). The C1q binding protein is inferred to form tetramers based on the properties of purified recombinant protein in vitro (Ghebrehiwet et al. 1994); the stoichiometry of the cell surface complex has not been determined directly.
  • Kininogen (high molecular weight kininogen; HK) associates with C1q binding protein on the cell surface in a reaction dependent on Zn++ (Joseph et al. 1996). In the body, the Zn++ needed to drive this reaction may be provided locally by Zn++ release from activated platelets (Mahdi et al. 2002). The C1q binding protein is inferred to form tetramers based on the properties of purified recombinant protein in vitro (Ghebrehiwet et al. 1994); the stoichiometry of the cell surface complex has not been determined directly.
activated kininogen C1q binding protein tetramerArrowREACT_2004 (Reactome)
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
activated protein CArrowREACT_374 (Reactome)
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
activated protein Cmim-catalysisREACT_1071 (Reactome)
  • Activated protein C cleaves peptide bonds in activated factor V (factor Va), converting it to an inactive form (factor Vi). The exact site(s) of cleavage are unknown. Protein S, on the endothelial cell surface, positively regulates this reaction. Although the mechanism of this regulation is unclear, the regulation is physiologically important, as people with reduced amounts of protein S, like people with reduced amounts of protein C, are susceptible to thromboembolism.
  • Activated protein C cleaves peptide bonds in activated factor V (factor Va), converting it to an inactive form (factor Vi). The exact site(s) of cleavage are unknown. Protein S, on the endothelial cell surface, positively regulates this reaction. Although the mechanism of this regulation is unclear, the regulation is physiologically important, as people with reduced amounts of protein S, like people with reduced amounts of protein C, are susceptible to thromboembolism.
activated thrombin thrombomodulinArrowREACT_1834 (Reactome)
  • Activated thrombin (factor IIa) binds to thrombomodulin at the external face of the plasma membrane, forming a thrombin:thrombomodulin complex. In this complexed form, the activity of thrombin towards protein C is greatly increased, and as thrombomodulin is particularly abundant on the surfaces of endothelial cells, this association plays a major role in restricting clot formation.
  • Activated thrombin (factor IIa) binds to thrombomodulin at the external face of the plasma membrane, forming a thrombin:thrombomodulin complex. In this complexed form, the activity of thrombin towards protein C is greatly increased, and as thrombomodulin is particularly abundant on the surfaces of endothelial cells, this association plays a major role in restricting clot formation.
activated thrombin thrombomodulinmim-catalysisREACT_374 (Reactome)
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
antithrombin III heparinArrowREACT_102 (Reactome)
  • Antithrombin III binds to membrane-associated heparin, e.g., on the surface of a normal endothelial cell. This binding event increases the affinity of antithrombin III for thrombin approximately 1000-fold.
  • Antithrombin III binds to membrane-associated heparin, e.g., on the surface of a normal endothelial cell. This binding event increases the affinity of antithrombin III for thrombin approximately 1000-fold.
antithrombin III heparinREACT_1822 (Reactome)
  • Activated thrombin binds to the antithrombin III:heparin complex on the cell surface.
  • Activated thrombin binds to the antithrombin III:heparin complex on the cell surface.
factor IX activation peptideArrowREACT_158 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface, catalyzes the formation of activated factor IX with high efficiency. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface, catalyzes the formation of activated factor IX with high efficiency. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
factor IX activation peptideArrowREACT_2073 (Reactome)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
factor IXaArrowREACT_158 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface, catalyzes the formation of activated factor IX with high efficiency. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface, catalyzes the formation of activated factor IX with high efficiency. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
factor IXaArrowREACT_2073 (Reactome)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
factor IXaREACT_112 (Reactome)
  • The activated forms of factors VIII and IX associate on a cell surface to form a complex that very efficiently catalyzes the activation of factor X, the so-called "intrinsic tenase complex". In vitro, negatively charged phospholipids can provide an appropriate surface. In the body, the surface is provided by the plasma membranes of activated platelets (Gilbert and Arena 1996).
  • The activated forms of factors VIII and IX associate on a cell surface to form a complex that very efficiently catalyzes the activation of factor X, the so-called "intrinsic tenase complex". In vitro, negatively charged phospholipids can provide an appropriate surface. In the body, the surface is provided by the plasma membranes of activated platelets (Gilbert and Arena 1996).
factor V activation peptideArrowREACT_708 (Reactome)
  • Activated thrombin (factor IIa) catalyzes the conversion of factor V to factor Va (activated factor V). The activation peptide released in this reaction has no known function.
  • Activated thrombin (factor IIa) catalyzes the conversion of factor V to factor Va (activated factor V). The activation peptide released in this reaction has no known function.
factor VIII von Willebrand factor multimerArrowREACT_531 (Reactome)
  • Factor VIII binds to von Willebrand factor to form a complex. This complex stabilizes factor VIII, which otherwise has a very short half-life in the blood.

    Factor VIII (Vehar et al. 1984) is a heterodimer containing a heavy and a light polypeptide chain, generated by the proteolytic cleavage of a single large precursor polypeptide. Several forms of the heavy chain are found in vivo, all functionally the same but differing in the amount of the B domain removed by proteolysis. The single form annotated here is the shortest one (Eaton et al. 1986; Hill-Eubanks et al. 1989).

    In vitro, von Willebrand factor (Titani et al. 1986) can form complexes with factor VIII with a 1:1 stoichiometry. The complexes that form in vivo, however, involve large multimers of von Willebrand factor and varied, but always low, proportions of factor VIII (Vlot et al. 1995). A stoichiometry of one molecule of factor VIII associated with 50 of von Willebrand factor is typical in vivo, and is used here to annotate the factor VIII:von Willebrand factor complex.

  • Factor VIII binds to von Willebrand factor to form a complex. This complex stabilizes factor VIII, which otherwise has a very short half-life in the blood.

    Factor VIII (Vehar et al. 1984) is a heterodimer containing a heavy and a light polypeptide chain, generated by the proteolytic cleavage of a single large precursor polypeptide. Several forms of the heavy chain are found in vivo, all functionally the same but differing in the amount of the B domain removed by proteolysis. The single form annotated here is the shortest one (Eaton et al. 1986; Hill-Eubanks et al. 1989).

    In vitro, von Willebrand factor (Titani et al. 1986) can form complexes with factor VIII with a 1:1 stoichiometry. The complexes that form in vivo, however, involve large multimers of von Willebrand factor and varied, but always low, proportions of factor VIII (Vlot et al. 1995). A stoichiometry of one molecule of factor VIII associated with 50 of von Willebrand factor is typical in vivo, and is used here to annotate the factor VIII:von Willebrand factor complex.

factor VIII von Willebrand factor multimerREACT_217 (Reactome)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
factor VIIIREACT_531 (Reactome)
  • Factor VIII binds to von Willebrand factor to form a complex. This complex stabilizes factor VIII, which otherwise has a very short half-life in the blood.

    Factor VIII (Vehar et al. 1984) is a heterodimer containing a heavy and a light polypeptide chain, generated by the proteolytic cleavage of a single large precursor polypeptide. Several forms of the heavy chain are found in vivo, all functionally the same but differing in the amount of the B domain removed by proteolysis. The single form annotated here is the shortest one (Eaton et al. 1986; Hill-Eubanks et al. 1989).

    In vitro, von Willebrand factor (Titani et al. 1986) can form complexes with factor VIII with a 1:1 stoichiometry. The complexes that form in vivo, however, involve large multimers of von Willebrand factor and varied, but always low, proportions of factor VIII (Vlot et al. 1995). A stoichiometry of one molecule of factor VIII associated with 50 of von Willebrand factor is typical in vivo, and is used here to annotate the factor VIII:von Willebrand factor complex.

  • Factor VIII binds to von Willebrand factor to form a complex. This complex stabilizes factor VIII, which otherwise has a very short half-life in the blood.

    Factor VIII (Vehar et al. 1984) is a heterodimer containing a heavy and a light polypeptide chain, generated by the proteolytic cleavage of a single large precursor polypeptide. Several forms of the heavy chain are found in vivo, all functionally the same but differing in the amount of the B domain removed by proteolysis. The single form annotated here is the shortest one (Eaton et al. 1986; Hill-Eubanks et al. 1989).

    In vitro, von Willebrand factor (Titani et al. 1986) can form complexes with factor VIII with a 1:1 stoichiometry. The complexes that form in vivo, however, involve large multimers of von Willebrand factor and varied, but always low, proportions of factor VIII (Vlot et al. 1995). A stoichiometry of one molecule of factor VIII associated with 50 of von Willebrand factor is typical in vivo, and is used here to annotate the factor VIII:von Willebrand factor complex.

factor VIIIa factor IXaArrowREACT_112 (Reactome)
  • The activated forms of factors VIII and IX associate on a cell surface to form a complex that very efficiently catalyzes the activation of factor X, the so-called "intrinsic tenase complex". In vitro, negatively charged phospholipids can provide an appropriate surface. In the body, the surface is provided by the plasma membranes of activated platelets (Gilbert and Arena 1996).
  • The activated forms of factors VIII and IX associate on a cell surface to form a complex that very efficiently catalyzes the activation of factor X, the so-called "intrinsic tenase complex". In vitro, negatively charged phospholipids can provide an appropriate surface. In the body, the surface is provided by the plasma membranes of activated platelets (Gilbert and Arena 1996).
factor VIIIa factor IXamim-catalysisREACT_1668 (Reactome)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor VIIIa B A3 acidic polypeptideArrowREACT_217 (Reactome)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
factor VIIIaArrowREACT_217 (Reactome)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
factor VIIIaREACT_112 (Reactome)
  • The activated forms of factors VIII and IX associate on a cell surface to form a complex that very efficiently catalyzes the activation of factor X, the so-called "intrinsic tenase complex". In vitro, negatively charged phospholipids can provide an appropriate surface. In the body, the surface is provided by the plasma membranes of activated platelets (Gilbert and Arena 1996).
  • The activated forms of factors VIII and IX associate on a cell surface to form a complex that very efficiently catalyzes the activation of factor X, the so-called "intrinsic tenase complex". In vitro, negatively charged phospholipids can provide an appropriate surface. In the body, the surface is provided by the plasma membranes of activated platelets (Gilbert and Arena 1996).
factor VIIaREACT_137 (Reactome)
  • Tissue factor exposed at the endothelial cell surface forms a complex with F7a (activated factor VII) from the plasma
  • Tissue factor exposed at the endothelial cell surface forms a complex with F7a (activated factor VII) from the plasma
factor VREACT_708 (Reactome)
  • Activated thrombin (factor IIa) catalyzes the conversion of factor V to factor Va (activated factor V). The activation peptide released in this reaction has no known function.
  • Activated thrombin (factor IIa) catalyzes the conversion of factor V to factor Va (activated factor V). The activation peptide released in this reaction has no known function.
factor VaArrowREACT_708 (Reactome)
  • Activated thrombin (factor IIa) catalyzes the conversion of factor V to factor Va (activated factor V). The activation peptide released in this reaction has no known function.
  • Activated thrombin (factor IIa) catalyzes the conversion of factor V to factor Va (activated factor V). The activation peptide released in this reaction has no known function.
factor VaREACT_675 (Reactome)
  • Factors Va and Xa associate on a membrane surface to form a complex in which the activity of factor Xa on prothrombin is greatly increased (Mann et al. 1988). The presence of negatively charged phospholipid in the membrane greatly facilitates this process, a feature that may contribute to its localization, as such phospholipids are normally on the cytosolic face of the plasma membrane (Devaux 1992), but could be exposed to the extracellular space following platelet activation or mechanical injury to endothelial cells.
  • Factors Va and Xa associate on a membrane surface to form a complex in which the activity of factor Xa on prothrombin is greatly increased (Mann et al. 1988). The presence of negatively charged phospholipid in the membrane greatly facilitates this process, a feature that may contribute to its localization, as such phospholipids are normally on the cytosolic face of the plasma membrane (Devaux 1992), but could be exposed to the extracellular space following platelet activation or mechanical injury to endothelial cells.
factor Vafactor ViArrowREACT_1071 (Reactome)
  • Activated protein C cleaves peptide bonds in activated factor V (factor Va), converting it to an inactive form (factor Vi). The exact site(s) of cleavage are unknown. Protein S, on the endothelial cell surface, positively regulates this reaction. Although the mechanism of this regulation is unclear, the regulation is physiologically important, as people with reduced amounts of protein S, like people with reduced amounts of protein C, are susceptible to thromboembolism.
  • Activated protein C cleaves peptide bonds in activated factor V (factor Va), converting it to an inactive form (factor Vi). The exact site(s) of cleavage are unknown. Protein S, on the endothelial cell surface, positively regulates this reaction. Although the mechanism of this regulation is unclear, the regulation is physiologically important, as people with reduced amounts of protein S, like people with reduced amounts of protein C, are susceptible to thromboembolism.
factor X activation peptideArrowREACT_1668 (Reactome)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor X activation peptideArrowREACT_245 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor X activation peptideArrowREACT_493 (Reactome)
  • Factor VII, bound to tissue factor at the endothelial cell surface, catalyzes the activation of factor X from plasma with moderate efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VII, bound to tissue factor at the endothelial cell surface, catalyzes the activation of factor X from plasma with moderate efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor XI GPIb-IX-V complexArrowREACT_177 (Reactome)
  • Plasma factor XI binds to the platelet glycoprotein Ib:IX:V complex (Baglia et al. 2002; Greengard et al. 1986). In the body, this reaction occurs specifically on the surfaces of activated platelets, but not on endothelial cells (Baird and Walsh 2002). The stoichiometry of the platelet glycoprotein Ib:IX:V complex has not been established directly, but is inferred from the relative abundances of its components in platelet membranes (Modderman et al. 1992; Shrimpton et al. 2002).
  • Plasma factor XI binds to the platelet glycoprotein Ib:IX:V complex (Baglia et al. 2002; Greengard et al. 1986). In the body, this reaction occurs specifically on the surfaces of activated platelets, but not on endothelial cells (Baird and Walsh 2002). The stoichiometry of the platelet glycoprotein Ib:IX:V complex has not been established directly, but is inferred from the relative abundances of its components in platelet membranes (Modderman et al. 1992; Shrimpton et al. 2002).
factor XI GPIb-IX-V complexfactor XIa

GPIb GPIX

GPV complex		ArrowREACT_1581 (Reactome)
  • Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). In the body, this reaction occurs on the surfaces of activated platelets (Baglia et al. 2002). Small quantities of factor XI can be activated in a reaction catalyzed by factor XIIa, to initiate formation of a fibrin clot. However, the efficient activation of larger quantities of factor XI, needed to propagate the blood clotting process, appears to be mediated by thrombin (Baglia and Walsh 2000; Gailani and Broze 1993; Naito and Fujikawa 1991; Oliver et al. 1999; Monroe et al. 2002).
  • Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). In the body, this reaction occurs on the surfaces of activated platelets (Baglia et al. 2002). Small quantities of factor XI can be activated in a reaction catalyzed by factor XIIa, to initiate formation of a fibrin clot. However, the efficient activation of larger quantities of factor XI, needed to propagate the blood clotting process, appears to be mediated by thrombin (Baglia and Walsh 2000; Gailani and Broze 1993; Naito and Fujikawa 1991; Oliver et al. 1999; Monroe et al. 2002).
factor XI GPIb-IX-V complexfactor XIa

GPIb GPIX

GPV complex		ArrowREACT_905 (Reactome)
  • Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). Chemically, this reaction involves the cleavage of a single peptide bond in each subunit of the factor XI homodimer; intra- and inter-chain disulfide bonds hold the resulting four polypeptides together (Bouma and Griffin 1977; Kurachi and Davie 1977; McMullen et al. 1991). In the body, this reaction occurs on the surfaces of activated platelets (Greengard et al. 1986; Baglia et al. 2002; Baird and Walsh 2002); when this reaction occurs as a step in the intrinsic ("contact") pathway of blood coagulation, it is catalyzed by activated factor XIIa (Kurachi and Davie 1977, Baglia and Walsh 2000) which in turn is generated through the interactions of factor XII, kallikrein, and kininogen on endothelial cell surfaces (Schmaier 2004).
  • Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). Chemically, this reaction involves the cleavage of a single peptide bond in each subunit of the factor XI homodimer; intra- and inter-chain disulfide bonds hold the resulting four polypeptides together (Bouma and Griffin 1977; Kurachi and Davie 1977; McMullen et al. 1991). In the body, this reaction occurs on the surfaces of activated platelets (Greengard et al. 1986; Baglia et al. 2002; Baird and Walsh 2002); when this reaction occurs as a step in the intrinsic ("contact") pathway of blood coagulation, it is catalyzed by activated factor XIIa (Kurachi and Davie 1977, Baglia and Walsh 2000) which in turn is generated through the interactions of factor XII, kallikrein, and kininogen on endothelial cell surfaces (Schmaier 2004).
factor XIII A chain activation peptideArrowREACT_1536 (Reactome)
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
factor XIII cleaved tetramerArrowREACT_1536 (Reactome)
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
factor XIII cleaved tetramerREACT_1314 (Reactome)
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
factor XIIIREACT_1536 (Reactome)
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
factor XIIIaArrowREACT_1314 (Reactome)
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
  • Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa).
factor XIIIamim-catalysisREACT_1852 (Reactome)
  • Fibrin multimers are stabilized by the formation of multiple covalent crosslinks between the side chains of specific lysine and glutamine residues in fibrinogen alpha and gamma chains, catalyzed by factor XIIIa.
  • Fibrin multimers are stabilized by the formation of multiple covalent crosslinks between the side chains of specific lysine and glutamine residues in fibrinogen alpha and gamma chains, catalyzed by factor XIIIa.
factor XIIa C1InhArrowREACT_825 (Reactome)
  • Activated factor XII (factor XIIa) binds to C1Inh (C1 inhibitor - Bock et al. 1986) to form a stable, inactive complex (Schneider et al. 1973). While several protease inhibitors can form stable complexes with XIIa in vitro, only C1Inh does so to a significant extent under normal conditions in vivo (Pixley et al. 1985).
  • Activated factor XII (factor XIIa) binds to C1Inh (C1 inhibitor - Bock et al. 1986) to form a stable, inactive complex (Schneider et al. 1973). While several protease inhibitors can form stable complexes with XIIa in vitro, only C1Inh does so to a significant extent under normal conditions in vivo (Pixley et al. 1985).
factor XIIaREACT_825 (Reactome)
  • Activated factor XII (factor XIIa) binds to C1Inh (C1 inhibitor - Bock et al. 1986) to form a stable, inactive complex (Schneider et al. 1973). While several protease inhibitors can form stable complexes with XIIa in vitro, only C1Inh does so to a significant extent under normal conditions in vivo (Pixley et al. 1985).
  • Activated factor XII (factor XIIa) binds to C1Inh (C1 inhibitor - Bock et al. 1986) to form a stable, inactive complex (Schneider et al. 1973). While several protease inhibitors can form stable complexes with XIIa in vitro, only C1Inh does so to a significant extent under normal conditions in vivo (Pixley et al. 1985).
factor XIIamim-catalysisREACT_905 (Reactome)
  • Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). Chemically, this reaction involves the cleavage of a single peptide bond in each subunit of the factor XI homodimer; intra- and inter-chain disulfide bonds hold the resulting four polypeptides together (Bouma and Griffin 1977; Kurachi and Davie 1977; McMullen et al. 1991). In the body, this reaction occurs on the surfaces of activated platelets (Greengard et al. 1986; Baglia et al. 2002; Baird and Walsh 2002); when this reaction occurs as a step in the intrinsic ("contact") pathway of blood coagulation, it is catalyzed by activated factor XIIa (Kurachi and Davie 1977, Baglia and Walsh 2000) which in turn is generated through the interactions of factor XII, kallikrein, and kininogen on endothelial cell surfaces (Schmaier 2004).
  • Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). Chemically, this reaction involves the cleavage of a single peptide bond in each subunit of the factor XI homodimer; intra- and inter-chain disulfide bonds hold the resulting four polypeptides together (Bouma and Griffin 1977; Kurachi and Davie 1977; McMullen et al. 1991). In the body, this reaction occurs on the surfaces of activated platelets (Greengard et al. 1986; Baglia et al. 2002; Baird and Walsh 2002); when this reaction occurs as a step in the intrinsic ("contact") pathway of blood coagulation, it is catalyzed by activated factor XIIa (Kurachi and Davie 1977, Baglia and Walsh 2000) which in turn is generated through the interactions of factor XII, kallikrein, and kininogen on endothelial cell surfaces (Schmaier 2004).
factor XIIfactor XIIaArrowREACT_1455 (Reactome)
  • Cleavage of a single peptide bond converts factor XII to activated factor XII (factor XIIa) (Fujikawa and McMullen 1983; McMullen and Fujikawa 1985). Identification of the catalytic activity or activities responsible for this cleavage has not been straightforward. Studies in vitro have demonstrated the autoactivation of factor XII as well as activation by kallikrein. Both reactions require the presence of negatively charged surfaces and are accelerated in the presence of kininogen (high molecular weight kininogen, HK) (Griffin and Cochrane 1976; Meier et al. 1977; Silverberg et al. 1980). Recent work suggests that factor XII activation in vivo may occur primarily on endothelial cell surfaces and that, as in vitro, association with kininogen may accelerate the reaction (Mahdi et al. 2002; Schmaier 2004), although alternative pathways and alternative mechanisms for associating factor XII with the cell surface have not been excluded (Joseph et al. 2001).
  • Cleavage of a single peptide bond converts factor XII to activated factor XII (factor XIIa) (Fujikawa and McMullen 1983; McMullen and Fujikawa 1985). Identification of the catalytic activity or activities responsible for this cleavage has not been straightforward. Studies in vitro have demonstrated the autoactivation of factor XII as well as activation by kallikrein. Both reactions require the presence of negatively charged surfaces and are accelerated in the presence of kininogen (high molecular weight kininogen, HK) (Griffin and Cochrane 1976; Meier et al. 1977; Silverberg et al. 1980). Recent work suggests that factor XII activation in vivo may occur primarily on endothelial cell surfaces and that, as in vitro, association with kininogen may accelerate the reaction (Mahdi et al. 2002; Schmaier 2004), although alternative pathways and alternative mechanisms for associating factor XII with the cell surface have not been excluded (Joseph et al. 2001).
factor XIREACT_177 (Reactome)
  • Plasma factor XI binds to the platelet glycoprotein Ib:IX:V complex (Baglia et al. 2002; Greengard et al. 1986). In the body, this reaction occurs specifically on the surfaces of activated platelets, but not on endothelial cells (Baird and Walsh 2002). The stoichiometry of the platelet glycoprotein Ib:IX:V complex has not been established directly, but is inferred from the relative abundances of its components in platelet membranes (Modderman et al. 1992; Shrimpton et al. 2002).
  • Plasma factor XI binds to the platelet glycoprotein Ib:IX:V complex (Baglia et al. 2002; Greengard et al. 1986). In the body, this reaction occurs specifically on the surfaces of activated platelets, but not on endothelial cells (Baird and Walsh 2002). The stoichiometry of the platelet glycoprotein Ib:IX:V complex has not been established directly, but is inferred from the relative abundances of its components in platelet membranes (Modderman et al. 1992; Shrimpton et al. 2002).
factor XIa

GPIb GPIX

GPV complex		mim-catalysisREACT_2073 (Reactome)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
  • Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.)
factor XREACT_1668 (Reactome)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor XREACT_245 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor XREACT_493 (Reactome)
  • Factor VII, bound to tissue factor at the endothelial cell surface, catalyzes the activation of factor X from plasma with moderate efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VII, bound to tissue factor at the endothelial cell surface, catalyzes the activation of factor X from plasma with moderate efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor XaArrowREACT_1668 (Reactome)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor XaArrowREACT_245 (Reactome)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor XaArrowREACT_493 (Reactome)
  • Factor VII, bound to tissue factor at the endothelial cell surface, catalyzes the activation of factor X from plasma with moderate efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
  • Factor VII, bound to tissue factor at the endothelial cell surface, catalyzes the activation of factor X from plasma with moderate efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.)
factor XaREACT_654 (Reactome)
  • TFPI binds to the factor VIIa:TF complex and to factor Xa at the endothelial surface, forming a stable heterotetrameric complex in which factor VIIa is catalytically inactive.
  • TFPI binds to the factor VIIa:TF complex and to factor Xa at the endothelial surface, forming a stable heterotetrameric complex in which factor VIIa is catalytically inactive.
factor XaREACT_675 (Reactome)
  • Factors Va and Xa associate on a membrane surface to form a complex in which the activity of factor Xa on prothrombin is greatly increased (Mann et al. 1988). The presence of negatively charged phospholipid in the membrane greatly facilitates this process, a feature that may contribute to its localization, as such phospholipids are normally on the cytosolic face of the plasma membrane (Devaux 1992), but could be exposed to the extracellular space following platelet activation or mechanical injury to endothelial cells.
  • Factors Va and Xa associate on a membrane surface to form a complex in which the activity of factor Xa on prothrombin is greatly increased (Mann et al. 1988). The presence of negatively charged phospholipid in the membrane greatly facilitates this process, a feature that may contribute to its localization, as such phospholipids are normally on the cytosolic face of the plasma membrane (Devaux 1992), but could be exposed to the extracellular space following platelet activation or mechanical injury to endothelial cells.
factor Xamim-catalysisREACT_1097 (Reactome)
  • Membrane-bound factor Xa catalyzes the activation of small amounts of thrombin. The amino terminal portion of prothrombin is released as an activation peptide, which can be cleaved further by activated thrombin. Neither the full-length activation peptide nor its cleavage products have known functions.
  • Membrane-bound factor Xa catalyzes the activation of small amounts of thrombin. The amino terminal portion of prothrombin is released as an activation peptide, which can be cleaved further by activated thrombin. Neither the full-length activation peptide nor its cleavage products have known functions.
factor Xamim-catalysisREACT_9 (Reactome)
  • Factor Xa catalyzes the activation of factor VII from plasma.
  • Factor Xa catalyzes the activation of factor VII from plasma.
fibrin monomerArrowREACT_214 (Reactome)
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
  • The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively).
fibrin monomerfibrin multimerArrowREACT_1329 (Reactome)
  • Fibrin monomers rapidly and spontaneously associate into large multimers, binding to one another via sites created by fibrinopeptide release (Laudano and Doolittelle 1980). The process of multimerization, and the range of multimer structures that can form in vivo and in vitro, have been studied in detail (Doolittle 1984). Here, multimer size has arbitrarily been set to three fibrin monomers.
  • Fibrin monomers rapidly and spontaneously associate into large multimers, binding to one another via sites created by fibrinopeptide release (Laudano and Doolittelle 1980). The process of multimerization, and the range of multimer structures that can form in vivo and in vitro, have been studied in detail (Doolittle 1984). Here, multimer size has arbitrarily been set to three fibrin monomers.
fibrin multimer, crosslinkedArrowREACT_1852 (Reactome)
  • Fibrin multimers are stabilized by the formation of multiple covalent crosslinks between the side chains of specific lysine and glutamine residues in fibrinogen alpha and gamma chains, catalyzed by factor XIIIa.
  • Fibrin multimers are stabilized by the formation of multiple covalent crosslinks between the side chains of specific lysine and glutamine residues in fibrinogen alpha and gamma chains, catalyzed by factor XIIIa.
fibrin multimerArrowREACT_1536 (Reactome)
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
  • Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive.
fibrin multimerREACT_1852 (Reactome)
  • Fibrin multimers are stabilized by the formation of multiple covalent crosslinks between the side chains of specific lysine and glutamine residues in fibrinogen alpha and gamma chains, catalyzed by factor XIIIa.
  • Fibrin multimers are stabilized by the formation of multiple covalent crosslinks between the side chains of specific lysine and glutamine residues in fibrinogen alpha and gamma chains, catalyzed by factor XIIIa.
kallikrein C1InhArrowREACT_1486 (Reactome)
  • Activated kallikrein binds to C1Inh (plasma protease C1 inhibitor) (Bock et al. 1986), forming a stable and enzymatically inactive complex. This reaction appears to be the major means by which kallikrein is inactivated (kallikrein can also be inactivated by binding to alpha2-macroglobulin) (Harpel et al. 1985; Ratnoff et al. 1969).
  • Activated kallikrein binds to C1Inh (plasma protease C1 inhibitor) (Bock et al. 1986), forming a stable and enzymatically inactive complex. This reaction appears to be the major means by which kallikrein is inactivated (kallikrein can also be inactivated by binding to alpha2-macroglobulin) (Harpel et al. 1985; Ratnoff et al. 1969).
kallikrein alpha2-macroglobulinArrowREACT_25 (Reactome)
  • Activated kallikrein binds to alpha2-macroglobulin (Sottrup-Jensen et al. 1984), forming a stable and enzymatically inactive complex. Under normal conditions in vivo, this reaction appears to be responsible for the inactivation of about 1/6 of activated kallikrein (with C1Inh responsible for the inactivation of about 5/6) (Harpel et al. 1985).
  • Activated kallikrein binds to alpha2-macroglobulin (Sottrup-Jensen et al. 1984), forming a stable and enzymatically inactive complex. Under normal conditions in vivo, this reaction appears to be responsible for the inactivation of about 1/6 of activated kallikrein (with C1Inh responsible for the inactivation of about 5/6) (Harpel et al. 1985).
kallikrein

kininogen

C1q binding protein tetramer		REACT_2004 (Reactome)
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
kallikrein

kininogen

C1q binding protein tetramer		mim-catalysisREACT_1455 (Reactome)
  • Cleavage of a single peptide bond converts factor XII to activated factor XII (factor XIIa) (Fujikawa and McMullen 1983; McMullen and Fujikawa 1985). Identification of the catalytic activity or activities responsible for this cleavage has not been straightforward. Studies in vitro have demonstrated the autoactivation of factor XII as well as activation by kallikrein. Both reactions require the presence of negatively charged surfaces and are accelerated in the presence of kininogen (high molecular weight kininogen, HK) (Griffin and Cochrane 1976; Meier et al. 1977; Silverberg et al. 1980). Recent work suggests that factor XII activation in vivo may occur primarily on endothelial cell surfaces and that, as in vitro, association with kininogen may accelerate the reaction (Mahdi et al. 2002; Schmaier 2004), although alternative pathways and alternative mechanisms for associating factor XII with the cell surface have not been excluded (Joseph et al. 2001).
  • Cleavage of a single peptide bond converts factor XII to activated factor XII (factor XIIa) (Fujikawa and McMullen 1983; McMullen and Fujikawa 1985). Identification of the catalytic activity or activities responsible for this cleavage has not been straightforward. Studies in vitro have demonstrated the autoactivation of factor XII as well as activation by kallikrein. Both reactions require the presence of negatively charged surfaces and are accelerated in the presence of kininogen (high molecular weight kininogen, HK) (Griffin and Cochrane 1976; Meier et al. 1977; Silverberg et al. 1980). Recent work suggests that factor XII activation in vivo may occur primarily on endothelial cell surfaces and that, as in vitro, association with kininogen may accelerate the reaction (Mahdi et al. 2002; Schmaier 2004), although alternative pathways and alternative mechanisms for associating factor XII with the cell surface have not been excluded (Joseph et al. 2001).
kallikrein

kininogen

C1q binding protein tetramer		mim-catalysisREACT_2004 (Reactome)
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
  • The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome.
prekallikrein

kininogen

C1q binding protein tetramer		ArrowREACT_1335 (Reactome)
  • Prekallikrein (PK) associates specifically with kininogen (HK) on cell surfaces. In vivo, this reaction may occur primarily on the surfaces of endothelial cells in response to platelet activation (Lin et al. 1997; Motta et al. 1998; Mahdi et al. 2003).
  • Prekallikrein (PK) associates specifically with kininogen (HK) on cell surfaces. In vivo, this reaction may occur primarily on the surfaces of endothelial cells in response to platelet activation (Lin et al. 1997; Motta et al. 1998; Mahdi et al. 2003).
prekallikrein

kininogen

C1q binding protein tetramer		kallikrein

kininogen

C1q binding protein tetramer		ArrowREACT_6 (Reactome)
  • Prekallikrein in a complex with kininogen and C1q binding protein on the plasma membrane is cleaved to generate active kallikrein, which remains bound to the complex. In the body, this reaction appears to occur on the surfaces of endothelial cells and may require the presence of activated platelets. Recent work indicates that the protease that cleaves prekallikrein under these conditions is prolylcarboxypeptidase. Although this enzyme was originally isolated from lysosomes (Odya et al. 1978; Tan et al. 1993), it is associated with plasma membranes of cultured human endothelial cells in vitro (Moreira et al. 2002; Shariat-Madar et al. 2002), and the purified recombinant enzyme efficiently cleaves prekallikrein (Shariat-Madar et al. 2004). In contrast factor XII, despite its activity on prekallikrein in vitro, appears not to be responsible for prekallikrein activation on the cell surface (Rojkjaer et al. 1998).
  • Prekallikrein in a complex with kininogen and C1q binding protein on the plasma membrane is cleaved to generate active kallikrein, which remains bound to the complex. In the body, this reaction appears to occur on the surfaces of endothelial cells and may require the presence of activated platelets. Recent work indicates that the protease that cleaves prekallikrein under these conditions is prolylcarboxypeptidase. Although this enzyme was originally isolated from lysosomes (Odya et al. 1978; Tan et al. 1993), it is associated with plasma membranes of cultured human endothelial cells in vitro (Moreira et al. 2002; Shariat-Madar et al. 2002), and the purified recombinant enzyme efficiently cleaves prekallikrein (Shariat-Madar et al. 2004). In contrast factor XII, despite its activity on prekallikrein in vitro, appears not to be responsible for prekallikrein activation on the cell surface (Rojkjaer et al. 1998).
prolylcarboxypeptidase dimermim-catalysisREACT_6 (Reactome)
  • Prekallikrein in a complex with kininogen and C1q binding protein on the plasma membrane is cleaved to generate active kallikrein, which remains bound to the complex. In the body, this reaction appears to occur on the surfaces of endothelial cells and may require the presence of activated platelets. Recent work indicates that the protease that cleaves prekallikrein under these conditions is prolylcarboxypeptidase. Although this enzyme was originally isolated from lysosomes (Odya et al. 1978; Tan et al. 1993), it is associated with plasma membranes of cultured human endothelial cells in vitro (Moreira et al. 2002; Shariat-Madar et al. 2002), and the purified recombinant enzyme efficiently cleaves prekallikrein (Shariat-Madar et al. 2004). In contrast factor XII, despite its activity on prekallikrein in vitro, appears not to be responsible for prekallikrein activation on the cell surface (Rojkjaer et al. 1998).
  • Prekallikrein in a complex with kininogen and C1q binding protein on the plasma membrane is cleaved to generate active kallikrein, which remains bound to the complex. In the body, this reaction appears to occur on the surfaces of endothelial cells and may require the presence of activated platelets. Recent work indicates that the protease that cleaves prekallikrein under these conditions is prolylcarboxypeptidase. Although this enzyme was originally isolated from lysosomes (Odya et al. 1978; Tan et al. 1993), it is associated with plasma membranes of cultured human endothelial cells in vitro (Moreira et al. 2002; Shariat-Madar et al. 2002), and the purified recombinant enzyme efficiently cleaves prekallikrein (Shariat-Madar et al. 2004). In contrast factor XII, despite its activity on prekallikrein in vitro, appears not to be responsible for prekallikrein activation on the cell surface (Rojkjaer et al. 1998).
protein CREACT_374 (Reactome)
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
  • Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
sequestered tissue factorPalmC-F3ArrowREACT_1596 (Reactome)
  • Tissue factor sequestered in the wall of a blood vessel is exposed to circulating blood when the endothelial lining of the vessel is injured.
  • Tissue factor sequestered in the wall of a blood vessel is exposed to circulating blood when the endothelial lining of the vessel is injured.
thrombin

antithrombin III

heparin		ArrowREACT_1822 (Reactome)
  • Activated thrombin binds to the antithrombin III:heparin complex on the cell surface.
  • Activated thrombin binds to the antithrombin III:heparin complex on the cell surface.
thrombin

antithrombin III

heparin		mim-catalysisREACT_1500 (Reactome)
  • Antithrombin III in the complex is cleaved by thrombin, thereupon undergoing a conformational change that stabilizes the thrombin:antithrombin III complex, trapping and inactivating the thrombin moiety.
  • Antithrombin III in the complex is cleaved by thrombin, thereupon undergoing a conformational change that stabilizes the thrombin:antithrombin III complex, trapping and inactivating the thrombin moiety.
thrombin

antithrombin III

heparin		thrombin

cleaved antithrombin III

heparin		ArrowREACT_1500 (Reactome)
  • Antithrombin III in the complex is cleaved by thrombin, thereupon undergoing a conformational change that stabilizes the thrombin:antithrombin III complex, trapping and inactivating the thrombin moiety.
  • Antithrombin III in the complex is cleaved by thrombin, thereupon undergoing a conformational change that stabilizes the thrombin:antithrombin III complex, trapping and inactivating the thrombin moiety.
thrombin

cleaved antithrombin III

heparin		REACT_1283 (Reactome)
  • The same conformational change that traps thrombin in its complex with cleaved antithrombin III also decreases the affinity of the latter for heparin, and the complex of cleaved antithrombin III and thrombin dissociates from the cell-bound heparin molecule.
  • The same conformational change that traps thrombin in its complex with cleaved antithrombin III also decreases the affinity of the latter for heparin, and the complex of cleaved antithrombin III and thrombin dissociates from the cell-bound heparin molecule.
thrombin cleaved antithrombin IIIArrowREACT_1283 (Reactome)
  • The same conformational change that traps thrombin in its complex with cleaved antithrombin III also decreases the affinity of the latter for heparin, and the complex of cleaved antithrombin III and thrombin dissociates from the cell-bound heparin molecule.
  • The same conformational change that traps thrombin in its complex with cleaved antithrombin III also decreases the affinity of the latter for heparin, and the complex of cleaved antithrombin III and thrombin dissociates from the cell-bound heparin molecule.
von Willibrand factor multimerArrowREACT_217 (Reactome)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
  • Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989)
von Willibrand factor multimerREACT_531 (Reactome)
  • Factor VIII binds to von Willebrand factor to form a complex. This complex stabilizes factor VIII, which otherwise has a very short half-life in the blood.

    Factor VIII (Vehar et al. 1984) is a heterodimer containing a heavy and a light polypeptide chain, generated by the proteolytic cleavage of a single large precursor polypeptide. Several forms of the heavy chain are found in vivo, all functionally the same but differing in the amount of the B domain removed by proteolysis. The single form annotated here is the shortest one (Eaton et al. 1986; Hill-Eubanks et al. 1989).

    In vitro, von Willebrand factor (Titani et al. 1986) can form complexes with factor VIII with a 1:1 stoichiometry. The complexes that form in vivo, however, involve large multimers of von Willebrand factor and varied, but always low, proportions of factor VIII (Vlot et al. 1995). A stoichiometry of one molecule of factor VIII associated with 50 of von Willebrand factor is typical in vivo, and is used here to annotate the factor VIII:von Willebrand factor complex.

  • Factor VIII binds to von Willebrand factor to form a complex. This complex stabilizes factor VIII, which otherwise has a very short half-life in the blood.

    Factor VIII (Vehar et al. 1984) is a heterodimer containing a heavy and a light polypeptide chain, generated by the proteolytic cleavage of a single large precursor polypeptide. Several forms of the heavy chain are found in vivo, all functionally the same but differing in the amount of the B domain removed by proteolysis. The single form annotated here is the shortest one (Eaton et al. 1986; Hill-Eubanks et al. 1989).

    In vitro, von Willebrand factor (Titani et al. 1986) can form complexes with factor VIII with a 1:1 stoichiometry. The complexes that form in vivo, however, involve large multimers of von Willebrand factor and varied, but always low, proportions of factor VIII (Vlot et al. 1995). A stoichiometry of one molecule of factor VIII associated with 50 of von Willebrand factor is typical in vivo, and is used here to annotate the factor VIII:von Willebrand factor complex.

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