Bravo2012 - Modelling blood coagulation factor Va inactivation by APC

  public model
Model Identifier
BIOMD0000000739
Short description
Mathematical model of blood coagulation factor Va and Va fragment inactivation by APC, reactions with Xa and prothrombinase-prothrombin complex formation.
Format
SBML (L2V4)
Related Publication
  • Modeling of human factor Va inactivation by activated protein C.
  • Bravo MC, Orfeo T, Mann KG, Everse SJ
  • BMC systems biology , 5/ 2012 , Volume 6 , pages: 45 , PubMed ID: 22607732
  • Cell and Molecular Biology Program, University of Vermont, 89 Beaumont Ave, Burlington, VT 05405, USA.
  • Because understanding of the inventory, connectivity and dynamics of the components characterizing the process of coagulation is relatively mature, it has become an attractive target for physiochemical modeling. Such models can potentially improve the design of therapeutics. The prothrombinase complex (composed of the protease factor (F)Xa and its cofactor FVa) plays a central role in this network as the main producer of thrombin, which catalyses both the activation of platelets and the conversion of fibrinogen to fibrin, the main substances of a clot. A key negative feedback loop that prevents clot propagation beyond the site of injury is the thrombin-dependent generation of activated protein C (APC), an enzyme that inactivates FVa, thus neutralizing the prothrombinase complex. APC inactivation of FVa is complex, involving the production of partially active intermediates and "protection" of FVa from APC by both FXa and prothrombin. An empirically validated mathematical model of this process would be useful in advancing the predictive capacity of comprehensive models of coagulation.A model of human APC inactivation of prothrombinase was constructed in a stepwise fashion by analyzing time courses of FVa inactivation in empirical reaction systems with increasing number of interacting components and generating corresponding model constructs of each reaction system. Reaction mechanisms, rate constants and equilibrium constants informing these model constructs were initially derived from various research groups reporting on APC inactivation of FVa in isolation, or in the presence of FXa or prothrombin. Model predictions were assessed against empirical data measuring the appearance and disappearance of multiple FVa degradation intermediates as well as prothrombinase activity changes, with plasma proteins derived from multiple preparations. Our work integrates previously published findings and through the cooperative analysis of in vitro experiments and mathematical constructs we are able to produce a final validated model that includes 24 chemical reactions and interactions with 14 unique rate constants which describe the flux in concentrations of 24 species.This study highlights the complexity of the inactivation process and provides a module of equations describing the Protein C pathway that can be integrated into existing comprehensive mathematical models describing tissue factor initiated coagulation.
Contributors
Submitter of the first revision: Matthew Roberts
Submitter of this revision: Krishna Kumar Tiwari
Modellers: Matthew Roberts, Krishna Kumar Tiwari

Metadata information

is (2 statements)
BioModels Database MODEL1807020001
BioModels Database BIOMD0000000739

isDescribedBy (1 statement)
PubMed 22607732

hasTaxon (1 statement)
Taxonomy Homo sapiens

isVersionOf (1 statement)
Gene Ontology blood coagulation

hasProperty (1 statement)
Mathematical Modelling Ontology Ordinary differential equation model

Curation status
Curated
Modelling approach(es)
ordinary differential equation model
Tags

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Model files
Bravo2012.xml SBML L2V4 representation of Bravo2012 - Modelling blood coagulation factor Va inactivation by APC. 87.97 KB Preview | Download

Additional files
Bravo2012.cps Copasi file with setup to reproduce figure 3A. Normalisation done on the data produced from simulation as per literature. 144.94 KB Preview | Download
Bravo2012.sedml SEDML file for the model 11.93 KB Preview | Download

  • Model originally submitted by : Matthew Roberts
  • Submitted: Jul 2, 2018 10:26:09 AM
  • Last Modified: Jul 1, 2019 2:42:04 PM
Revisions
  • Version: 4 public model Download this version
    • Submitted on: Jul 1, 2019 2:42:04 PM
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Automatically added model identifier BIOMD0000000739
  • Version: 2 public model Download this version
    • Submitted on: Jul 2, 2018 10:26:09 AM
    • Submitted by: Matthew Roberts
    • With comment: Edited model metadata online.

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Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
Va

Coagulation Factor V 		2.0E-8 mol
Va i 306 506

Coagulation Factor V 		0.0 mol
PT

Prothrombin 		0.0 mol
APC

Vitamin K-Dependent Protein C 		2.0E-9 mol
Va i 506

Coagulation Factor V 		0.0 mol
Va 307 679 709

Coagulation Factor V 		0.0 mol
Reactions
Reactions Rate Parameters
Va + PT => Va_PT compartment*(R17_kon*Va*PT-R17_koff*Va_PT) R17_koff = 70.0; R17_kon = 1.0E8
APC_Va_i_306 => APC + Va_i_306_506 compartment*R07_kcat*APC_Va_i_306 R07_kcat = 1.0
APC + Va => APC_Va compartment*(R01_kon*APC*Va-R01_koff*APC_Va) R01_koff = 0.7; R01_kon = 1.0E8
APC + Va_i_306 => APC_Va_i_306 compartment*(R05_kon*APC*Va_i_306-R05_koff*APC_Va_i_306) R05_kon = 1.0E8; R05_koff = 0.7
APC_Va => APC + Va_i_506 compartment*R02_kcat*APC_Va R02_kcat = 1.0
APC + Va_i_506 => APC_Va_i_506 compartment*(R04_kon*APC*Va_i_506-R04_koff*APC_Va_i_506) R04_koff = 0.7; R04_kon = 1.0E8
APC_Va_i_506 => APC + Va_i_306_506 compartment*R06_kcat*APC_Va_i_506 R06_kcat = 0.192
Xa_Va_i_306_PT => Xa + Va_1_306_Va_LC + Va_307_679_709 + PT compartment*R23_dis*Xa_Va_i_306_PT R23_dis = 0.0035
Xa_Va_i_306_506 + PT => Xa_Va_i_306_506_PT compartment*(R22_kon*Xa_Va_i_306_506*PT-R22_kon*Xa_Va_i_306_506_PT) R22_kon = 1.0E8
Curator's comment:
(added: 01 Jul 2019, 14:39:54, updated: 01 Jul 2019, 14:39:54)
Publication figure 3C, D and E reproduced as per literature. Figure data is generated using COPASI 4.24 (build 197). Data is later normalised to unity and plotted using xls. For other figures, attached cops file need to be modified the correct parameter.