{"database":"BioModels","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Txt":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=curation_notes.txt"],"Pdf":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362.pdf"],"Owl":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362-biopax3.owl","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362-biopax2.owl"],"Svg":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362.svg"],"Xml":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362_url.xml","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=manifest.xml"],"Other":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362.sci","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=curation_image.png","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=metadata.rdf","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362.png","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362-octave.m","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362-matlab.m","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362.ode","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362.m","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362_url.sedml","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000362?filename=BIOMD0000000362.vcml"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"submitter":["Michael Schubert"],"curationStatus":["Manually curated"],"modellingApproach":["ordinary differential equation model"],"levelVersion":["L2V4"],"full_dataset_link":["https://www.ebi.ac.uk/biomodels/BIOMD0000000362"],"publication_pubmed":["15039440"],"isPrivate":["false"],"repository":["BioModels"],"modelFormat":["SBML"],"omics_type":["Models"],"tokenised_name":["Butenas2004 BloodCoagulation"],"publication_year":["2004"],"submissionId":["MODEL1108260005"],"publication_authors":["Saulius Butenas, Thomas Orfeo, Matthew T Gissel, Kathleen E Brummel, Kenneth G Mann"],"first_author":["Saulius Butenas"],"publication":["15039440,\n                            The presence of activation peptides (AP) of the vitamin K-dependent proteins in the phlebotomy blood of human subjects suggests that active serine proteases may circulate in blood as well. The goal of the current study was to evaluate the influence of trace amounts of key coagulation proteases on tissue factor-independent thrombin generation using three models of coagulation. With procoagulants and select coagulation inhibitors at mean physiological concentrations, concentrations of factor IXa, factor Xa, and thrombin were set either equal to those of their AP or to values that would result based upon the rates of AP/enzyme generation and steady state enzyme inhibition. In the latter case, numerical simulation predicts that sufficient thrombin to produce a solid clot would be generated in approximately 2 min. Empirical data from the synthetic plasma suggest clotting times of 3-5 min, which are similar to that observed in contact pathway-inhibited whole blood (4.3 min) initiated with the same concentrations of factors IXa and Xa and thrombin. Numerical simulations performed with the concentrations of two of the enzymes held constant and one varied suggest that the presence of any pair of enzymes is sufficient to yield rapid clot formation. Modeling of states (numerical simulation and whole blood) where only one circulating protease is present at steady state concentration shows significant thrombin generation only for factor IXa. The addition of factor Xa and thrombin has little effect (if any) on thrombin generation induced by factor IXa alone. These data indicate that 1) concentrations of active coagulation enzymes circulating in vivo are significantly lower than can be predicted from the concentrations of their AP, and 2) expected trace amounts of factor IXa can trigger thrombin generation in the absence of tissue factor.. 22, 279.\n                            Department of Biochemistry, University of Vermont, Burlington, Vermont 05405-0068, USA."],"submitter_mail":["schubert@ebi.ac.uk"],"submitter_affiliation":["EBI"],"publicationId":["BIOMD0000000362"],"pubmed_abstract":["The activation of prothrombin, factor V, factor VIII, factor IX, and factor X by the tissue factor-factor VIIa complex, in vitro, in a system in which each precursor protein was present at plasma concentration, was evaluated using a combination of activity assays, immunoblots, active-site blots, and autoradiography. The thrombin generation curves observed were distinctly nonlinear and typically displayed a time lag in which little or no thrombin was observed. This was followed by an almost linear propagation phase of thrombin formation. The lag was a function of tissue factor/factor VIIa concentration and represented primarily the interval of factor V and factor VIII activation. The postlag propagation phase of thrombin generation was nearly independent of the initial activator (factor VIIa or tissue factor) concentration over a 10(3)-fold range in factor VIIa-tissue factor concentration. Maximum thrombin generation rates were observed when less than 1% of the factor IX and X present was activated but when nearly 100% activation of the cofactors, factor V and factor VIII, was achieved. Analyses of the activation pattern of factor V indicated that the cofactor is activated by both factor Xa and thrombin which are formed at low levels during the lag phase of the reaction. When the initial reaction mixture contained factor Va instead of factor V, the lag was substantially reduced. When factor V was deleted from the reaction mixture, no thrombin formation was observed. When either factor VII or factor IX was deleted from the reaction system, the propagation phase of thrombin formation (at 5 pM tissue factor-factor VIIa complex) was only one-third that observed for reactions which contained factor VIII and factor IX. The addition of factor XI to the experimental system increased the rate of thrombin formation by 15% during the propagation phase but had no effect upon the lag phase of the reaction. Our data suggest that normal hemostasis may be initiated by the factor VIIa-tissue factor complex and support the concept of multiple feedback reactions which amplify and propagate the hemostatic response.","The presence of activation peptides (AP) of the vitamin K-dependent proteins in the phlebotomy blood of human subjects suggests that active serine proteases may circulate in blood as well. The goal of the current study was to evaluate the influence of trace amounts of key coagulation proteases on tissue factor-independent thrombin generation using three models of coagulation. With procoagulants and select coagulation inhibitors at mean physiological concentrations, concentrations of factor IXa, factor Xa, and thrombin were set either equal to those of their AP or to values that would result based upon the rates of AP/enzyme generation and steady state enzyme inhibition. In the latter case, numerical simulation predicts that sufficient thrombin to produce a solid clot would be generated in approximately 2 min. Empirical data from the synthetic plasma suggest clotting times of 3-5 min, which are similar to that observed in contact pathway-inhibited whole blood (4.3 min) initiated with the same concentrations of factors IXa and Xa and thrombin. Numerical simulations performed with the concentrations of two of the enzymes held constant and one varied suggest that the presence of any pair of enzymes is sufficient to yield rapid clot formation. Modeling of states (numerical simulation and whole blood) where only one circulating protease is present at steady state concentration shows significant thrombin generation only for factor IXa. The addition of factor Xa and thrombin has little effect (if any) on thrombin generation induced by factor IXa alone. These data indicate that 1) concentrations of active coagulation enzymes circulating in vivo are significantly lower than can be predicted from the concentrations of their AP, and 2) expected trace amounts of factor IXa can trigger thrombin generation in the absence of tissue factor.","The effects of the stoichiometric inhibitors tissue factor pathway inhibitor (TFPI), antithrombin-III (AT-III) and heparin cofactor-II (HC-II) on thrombin generation were evaluated in a reaction system composed of coagulation factors VIIa, X, IX, VIII, and V and prothrombin initiated by tissue factor (TF) and phospholipids. Initiation of the reaction in the absence of inhibitors resulted in explosive thrombin generation for factor VIIa.TF concentrations varying from 100 to 0.25 pM with the lag time or initiation phase of thrombin generation increasing from 0 to 180 s with decreasing factor VIIa.TF concentrations. During the propagation phase, prothrombin is quantitatively activated to 1.4 micro;M alpha-thrombin. At normal plasma concentration (2.5 nM) full-length recombinant TFPI prolonged the initiation phase of thrombin generation 2-fold, and the rate of thrombin generation in the propagation phase of the reaction was 25-50% that of the uninhibited reaction when the reaction was initiated with 1.25-20 pM factor VIIa.TF. Inhibition of the reaction by TFPI is associated with a delay in factor V activation. In the presence of TFPI no explosive thrombin generation was observed when factor VIII was omitted from reactions initiated by factor VIIa.TF concentrations </=20 pM. This indicates that in the presence of TFPI the factor IXa.factor VIIIa pathway becomes essential at low factor VIIa.TF concentrations. In the reconstituted system, AT-III (3.4 micro;M) did not prolong the initiation phase of thrombin generation when the reaction was initiated with 1.25 pM factor VIIa.TF, nor did AT-III delay factor V activation. The rate of thrombin formation in the presence of AT-III was reduced to 30% that of the uninhibited reaction, and the alpha-thrombin formed was rapidly inhibited subsequent to its generation. The addition of HC-II alone at its physiological concentration (1.38 micro;M) to the procoagulant mixture did not alter the rate or extent of thrombin generation. Subsequently, the thrombin formed was slowly inhibited by HC-II. The slow inactivation of thrombin by HC-II does not contribute to thrombin inhibition in the presence of AT-III. In contrast, the combination of physiological levels of AT-III and TFPI inhibited explosive thrombin generation initiated by 1.25 pM factor VIIa.TF completely. The absence of prothrombin consumption indicated that the combination of TFPI and AT-III is able to prevent the formation of prothrombinase activity at low factor VIIa.TF concentrations. The data indicate that TFPI potentiates the action of AT-III by decreasing the rate of formation and thus the amount of catalyst formed in the reaction, enabling AT-III to effectively scavenge the limited traces of factor IXa and factor Xa formed in the presence of TFPI. The initiation of thrombin generation by increasing factor VIIa.TF concentrations in the presence of physiological concentrations of TFPI and AT-III showed dramatic changes in the maximal rates of thrombin generation over small changes in initiator concentration. These data demonstrate that significant thrombin generation becomes a \"threshold-limited\" event with regard to the initiating factor VIIa.TF concentration in the presence of TFPI and AT-III."],"pubmed_title":["Regulation of tissue factor initiated thrombin generation by the stoichiometric inhibitors tissue factor pathway inhibitor, antithrombin-III, and heparin cofactor-II.","The significance of circulating factor IXa in blood.","A model for the tissue factor pathway to thrombin. I. An empirical study."],"pubmed_authors":["Lawson J H JH, Kalafatis M M, Stram S S, Mann K G KG","van 't Veer C C, Mann K G KG","Butenas Saulius S, Orfeo Thomas T, Gissel Matthew T MT, Brummel Kathleen E KE, Mann Kenneth G KG"],"additional_accession":[]},"is_claimable":false,"name":"Butenas2004_BloodCoagulation","description":"\n      \n        This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.\nFor more information see the terms of use.\nTo cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.\n      \n    \n  ","dates":{"last_modification":"2024-08-21","publication":"2024-09-02","submission":"2011-08-26"},"accession":"BIOMD0000000362","cross_references":{"pubmed":["15039440","9020158","8083241"],"biomodels__db":["MODEL1108260005","BIOMD0000000362"],"go":["GO:0007596"],"taxonomy":["2759"],"uniprot":["P13726","P08709","P00742","P00740","P00734","P00451","P12259","P10646","P01008"]}}