Luan2007 - Blood coagulation model combining previous models and platelet activation

  public model
Model Identifier
MODEL1806050001
Short description
Mathematical model combining previous models (Jones1994, Leipoldt1995, Kuhursky2001, Hockin2002) into one model with platelet activation.
Format
SBML (L2V4)
Related Publication
  • Computationally derived points of fragility of a human cascade are consistent with current therapeutic strategies.
  • Luan D, Zai M, Varner JD
  • PLoS computational biology , 7/ 2007 , Volume 3 , Issue 7 , pages: e142 , PubMed ID: 17658944
  • Department of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA.
  • The role that mechanistic mathematical modeling and systems biology will play in molecular medicine and clinical development remains uncertain. In this study, mathematical modeling and sensitivity analysis were used to explore the working hypothesis that mechanistic models of human cascades, despite model uncertainty, can be computationally screened for points of fragility, and that these sensitive mechanisms could serve as therapeutic targets. We tested our working hypothesis by screening a model of the well-studied coagulation cascade, developed and validated from literature. The predicted sensitive mechanisms were then compared with the treatment literature. The model, composed of 92 proteins and 148 protein-protein interactions, was validated using 21 published datasets generated from two different quiescent in vitro coagulation models. Simulated platelet activation and thrombin generation profiles in the presence and absence of natural anticoagulants were consistent with measured values, with a mean correlation of 0.87 across all trials. Overall state sensitivity coefficients, which measure the robustness or fragility of a given mechanism, were calculated using a Monte Carlo strategy. In the absence of anticoagulants, fluid and surface phase factor X/activated factor X (fX/FXa) activity and thrombin-mediated platelet activation were found to be fragile, while fIX/FIXa and fVIII/FVIIIa activation and activity were robust. Both anti-fX/FXa and direct thrombin inhibitors are important classes of anticoagulants; for example, anti-fX/FXa inhibitors have FDA approval for the prevention of venous thromboembolism following surgical intervention and as an initial treatment for deep venous thrombosis and pulmonary embolism. Both in vitro and in vivo experimental evidence is reviewed supporting the prediction that fIX/FIXa activity is robust. When taken together, these results support our working hypothesis that computationally derived points of fragility of human relevant cascades could be used as a rational basis for target selection despite model uncertainty.
Contributors
Submitter of the first revision: Matthew Roberts
Submitter of this revision: Matthew Roberts
Modellers: Matthew Roberts

Metadata information

hasPart (4 statements)
BioModels Database BIOMD0000000335
BioModels Database MODEL1109150002
BioModels Database BIOMD0000000336
BioModels Database MODEL1109150000

isDescribedBy (1 statement)
PubMed 17658944

isVersionOf (1 statement)
Gene Ontology blood coagulation

hasProperty (1 statement)
Gene Ontology platelet activation

occursIn (1 statement)
Brenda Tissue Ontology blood plasma

Curation status
Non-curated
Tags

Connected external resources

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Model files
Luan2007.xml SBML L2V4 representation of Luan2007 - Blood coagulation model combining previous models and platelet activation 288.44 KB Preview | Download

Additional files
Luan2007.cps Despite given initial conditions in appendix, unable to reproduce simulation results in Fig 2 A-F. R88 has been changed since the product was listed as VIIIa-TF-ATIII when VIIa-TF was the one reactant. R26 and R42 encoded as irreversible reactions since only the one kinetic parameter is given. Not sure how to encode the initial platelet binding site concentration to be different for the activated and non-activated forms (conc. given in nM and fM). 98 species present while paper lists that there are 92. 470.81 KB Preview | Download

  • Model originally submitted by : Matthew Roberts
  • Submitted: Jun 5, 2018 4:30:06 PM
  • Last Modified: Jun 5, 2018 4:30:06 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Jun 5, 2018 4:30:06 PM
    • Submitted by: Matthew Roberts
    • With comment: Edited model metadata online.