BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL1807240001?filename=Orfeo2010.xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL1807240001?filename=fig.jpghttps://www.ebi.ac.uk/biomodels/model/download/MODEL1807240001?filename=Orfeo2010.cpsprimaryOK200Matthew RobertsNon-curatedL2V4https://www.ebi.ac.uk/biomodels/MODEL180724000120492473falseBioModelsModelsSBMLOrfeo2010 Simulating the effects of fondaparinux and Rivaroxaban on thrombin generation2010MODEL1807240001Orfeo T, Butenas S, Brummel-Ziedins KE, Gissel M, Mann KGOrfeo T20492473,
Therapeutic agents that regulate blood coagulation are critical to the management of thrombotic disorders, with the selective targeting of factor (F) Xa emerging as a promising approach.To assess anticoagulant strategies targeting FXa.A deterministic computational model of tissue factor (Tf)-initiated thrombin generation and two empirical experimental systems (a synthetic coagulation proteome reconstruction using purified proteins and a whole blood model) were used to evaluate clinically relevant examples of the two available types of FXa-directed anticoagulants [an antithrombin (AT)-dependent agent, fondaparinux, and an AT-independent inhibitor, Rivaroxaban] in experimental regimens relevant to long-term (suppression of new Tf-initiated events) and acute (suppression of ongoing coagulation processes) clinical applications.Computational representations of each anticoagulant's efficacy in suppressing thrombin generation over a range of anticoagulant concentrations in both anticoagulation regimens were validated by results from corresponding empirical reconstructions and were consistent with those recommended for long-term and acute clinical applications, respectively. All three model systems suggested that Rivaroxaban would prove more effective in the suppression of an ongoing coagulation process than fondaparinux, reflecting its much higher reactivity toward the prothrombinase complex.The success of fondaparinux in acute settings in vivo is not explained solely by its properties as an FXa inhibitor. We have reported that FIXa contributes to the long-term capacity of clot-associated catalysts to restart a coagulation process, suggesting that the enhanced anti-FIXa activity of fondaparinux-AT may be critical to its success in acute settings in vivo.. 8, 8.
Department of Biochemistry, University of Vermont, Colchester, VT, USA.mroberts@ebi.ac.ukEMBL-EBI<h4>Background</h4>Therapeutic agents that regulate blood coagulation are critical to the management of thrombotic disorders, with the selective targeting of factor (F) Xa emerging as a promising approach.<h4>Objective</h4>To assess anticoagulant strategies targeting FXa.<h4>Methods</h4>A deterministic computational model of tissue factor (Tf)-initiated thrombin generation and two empirical experimental systems (a synthetic coagulation proteome reconstruction using purified proteins and a whole blood model) were used to evaluate clinically relevant examples of the two available types of FXa-directed anticoagulants [an antithrombin (AT)-dependent agent, fondaparinux, and an AT-independent inhibitor, Rivaroxaban] in experimental regimens relevant to long-term (suppression of new Tf-initiated events) and acute (suppression of ongoing coagulation processes) clinical applications.<h4>Results</h4>Computational representations of each anticoagulant's efficacy in suppressing thrombin generation over a range of anticoagulant concentrations in both anticoagulation regimens were validated by results from corresponding empirical reconstructions and were consistent with those recommended for long-term and acute clinical applications, respectively. All three model systems suggested that Rivaroxaban would prove more effective in the suppression of an ongoing coagulation process than fondaparinux, reflecting its much higher reactivity toward the prothrombinase complex.<h4>Conclusion</h4>The success of fondaparinux in acute settings in vivo is not explained solely by its properties as an FXa inhibitor. We have reported that FIXa contributes to the long-term capacity of clot-associated catalysts to restart a coagulation process, suggesting that the enhanced anti-FIXa activity of fondaparinux-AT may be critical to its success in acute settings in vivo.Anticoagulation by factor Xa inhibitors.Orfeo T T, Butenas S S, Brummel-Ziedins K E KE, Gissel M M, Mann K G KG3S, Thrombase, Thrombin-JMI, thrombin, (2S, BAY 59 7939, Thrombin, Xarelto, Thrombostat, Quixidar, Cf2, 6S)-4-hydroxy-6-methoxy-5-(sulfoamino)-2-(sulfooxymethyl)oxan-3-yl)oxy-5-sulfooxyoxan-3-yl)oxy-5-(sulfoamino)-4-sulfooxy-2-(sulfooxymethyl)oxan-3-yl)oxy-3-((2R, 3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide, alpha-Thrombin, Cf-2., 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1, 5-dihydroxyoxane-2-carboxylic acid, Arixtra, 4R, beta, 4S, BAY 597939, BAY 59-7939, FII, JMI, 6R)-4, Thrombinar, 5-dihydroxy-3-(sulfoamino)-6-(sulfooxymethyl)oxan-2-yl)oxy-4, 6R)-2-carboxy-4-hydroxy-6-((2R, Thrombin JMI, Fondaparinux Sodium, 6R)-6-((2R, gamma-Thrombin, beta-Thrombin, 5R, 5S, 3Rprojections, other disease, anticoagulante, artificial sequence, Procedures, Activity, Anticoagulation, experimental, lamellae, Clotting, Blood, Cf2, Quixidar, coagulated blood, Gene, anticoagulants, 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1, Anticoagulant Drugs, process of organ, ter, protrusion, clot, Agent, Anticoagulants, lamella, Indirect Thrombin Inhibitors, Techniques, BAY 59-7939, diseases, 6R)-4, Method, responsivity, Studies, Gene Products, Alleviating interaction, disease or disorder, diseases and disorders, Inhibitors, gamma-Thrombin, 6R)-6-((2R, synthetic genetic interaction (sensu inequality), Thrombin Inhibitors, Technique, Drugs, portion of blood, portion of tissue, reactivity, human disease, methods, Anticoagulant, Xarelto, thrombus, Thrombostat, experimental section, long, Tissue, inhibiteur, alpha-Thrombin, synthetic genetic interaction defined by inequality, proteins, Blood Clotting, procedures, ridges, suppressive genetic interaction (sensu inequality), 5-dihydroxyoxane-2-carboxylic acid, BAY 597939, non-neoplastic, Study, DmelCG4216, JMI, inhibidor, Methodological Studies, Bsg75C, papilla, Thrombin JMI, 6R)-2-carboxy-4-hydroxy-6-((2R, disorder, Homo sapiens disease, Cf-2, associated, laminae, 3R, 3S, Thrombase, inhibitors, Thrombin-JMI, hemostatic plug, Coagulation, anatomical protrusion, Anticoagulant Drug, Thrombin, whole blood, (2S, Acute onset., vertebrate blood, anatomical process, 3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide, Proteins, disorders, lamina, total expressed protein, flanges, inhibitor, artificial gene, medical condition, Procedure, synthetic DNA, results, Arixtra, 4R, 4S, Acute onset, Indirect, Thrombinar, 5-dihydroxy-3-(sulfoamino)-6-(sulfooxymethyl)oxan-2-yl)oxy-4, Term, Anticoagulant Agents, FXA, Protein, Blood Clottings, shelf, tissue portion, synthetic, condition, Fondaparinux Sodium, simple tissue, background, blood clotting, techniques, fibrin clot, flange, 5R, organ process, 5S, thrombin, clotting, BAY 59 7939, shelves, 6S)-4-hydroxy-6-methoxy-5-(sulfoamino)-2-(sulfooxymethyl)oxan-3-yl)oxy-5-sulfooxyoxan-3-yl)oxy-5-(sulfoamino)-4-sulfooxy-2-(sulfooxymethyl)oxan-3-yl)oxy-3-((2R, FX, CG4216, Anticoagulation Agents, Methodological, Methodological Study, synthetic constructs, projection, ridge, introduction, beta, experimental procedures, Drug, Protein Gene Products, Gene Proteins, processes, process, disease, Anticoagulant Agent, SYNTHETIC CONSTRUCT sequences, FII, Agents, spine, artificial, processus, beta-Thrombin, response, Proteomes, General activity, methodology, Indirect Thrombin3S, BAY 597939., Coagulation, artificial sequence, Unfractionated Heparin, (2S, THPH7, Clotting, Blood, Quixidar, 3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide, artificial gene, synthetic DNA, 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1, Arixtra, 4R, 4S, BAY 59-7939, At-3, 6R)-4, 5-dihydroxy-3-(sulfoamino)-6-(sulfooxymethyl)oxan-2-yl)oxy-4, ATIII, AI114908, Blood Clottings, synthetic, Fondaparinux Sodium, 6R)-6-((2R, Liquaemin, Sodium, blood clotting, synthetic genetic interaction (sensu inequality), Unfractionated, 5R, 5S, At3, Heparinic Acid, clotting, alpha Heparin, BAY 59 7939, Xarelto, ligand, 6S)-4-hydroxy-6-methoxy-5-(sulfoamino)-2-(sulfooxymethyl)oxan-3-yl)oxy-5-sulfooxyoxan-3-yl)oxy-5-(sulfoamino)-4-sulfooxy-2-(sulfooxymethyl)oxan-3-yl)oxy-3-((2R, synthetic genetic interaction defined by inequality, Blood Clotting, synthetic constructs, 5-dihydroxyoxane-2-carboxylic acid, Serpin C1, BAY 597939, AT3, SYNTHETIC CONSTRUCT sequences, alpha-Heparin, 6R)-2-carboxy-4-hydroxy-6-((2R, artificial, Sodium Heparin, AT3D, Heparin, Heparin Sodium, 3RFactor Xa Inhibitor, Anticoagulants, Xa Inhibitor, Direct-Acting Oral, Oral Anticoagulant, Factor Xa, Direct Acting Oral Anticoagulants, Direct-Acting Oral Anticoagulants, Direct-Acting Oral Anticoagulant, Anticoagulant, Direct Acting Oral Anticoagulant, Direct-Acting, Factor, Inhibitor, Direct Factor Xa Inhibitor., Oral Anticoagulants, Direct Factor Xa InhibitorsfalseOrfeo2010 - Simulating the effects of fondaparinux and Rivaroxaban on thrombin generationReused mathematical model (Hockin et al., 2002) of blood coagulation simulating the effects of coagulation factor inhibitors, fondaparinux (synthetic heparin) and Rivaroxaban. Fondaparinux (Fpx) simulated to reversibly bind with ATIII before irreversibly binding to Xa, IXa, mIIa, TF:VIIa, Xa:Va and IIa. Rivaroxaban simulated to bind reversibly to Xa and Xa:Va.2018-07-242018-07-242018-07-24MODEL1807240001SBO:0000036SBO:0000038SBO:0000035SBO:000003920492473CHEBI:61033CHEBI:68579BIOMD0000000335GO:0007596D01844D070869606BTO:0000131P00742P00451P00740P12259P10646P01008P13726P08709P00734