Ghaffari2019 - Thrombomodulin Gene Expression after Retinoic Acid Treatment for Cancer Patients with Coagulation Disorders

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Publication includes a mathematical model for how retinoic acid affects thrombomodulin gene and mRNA expression as well as a two-compartment pharmacokinetic model for retinoic acid.
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  • Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients.
  • Ghaffari H, Varner JD, Petzold LR
  • Theoretical biology & medical modelling , 2/ 2019 , Volume 16 , Issue 1 , pages: 3 , PubMed ID: 30764845
  • Department of Mechanical Engineering, University of California Santa Barbara, Santa Barbara, CA, 93106, USA.
  • BACKGROUND:Clinical studies have shown that all-trans retinoic acid (RA), which is often used in treatment of cancer patients, improves hemostatic parameters and bleeding complications such as disseminated intravascular coagulation (DIC). However, the mechanisms underlying this improvement have yet to be elucidated. In vitro studies have reported that RA upregulates thrombomodulin (TM) expression on the endothelial cell surface. The objective of this study was to investigate how and to what extent the TM concentration changes after RA treatment in cancer patients, and how this variation influences the blood coagulation cascade. RESULTS:In this study, we introduced an ordinary differential equation (ODE) model of gene expression for the RA-induced upregulation of TM concentration. Coupling the gene expression model with a two-compartment pharmacokinetic model of RA, we obtained the time-dependent changes in TM and thrombomodulin-mRNA (TMR) concentrations following oral administration of RA. Our results indicated that the TM concentration reached its peak level almost 14 h after taking a single oral dose (110 [Formula: see text]) of RA. Continuous treatment with RA resulted in oscillatory expression of TM on the endothelial cell surface. We then coupled the gene expression model with a mechanistic model of the coagulation cascade, and showed that the elevated levels of TM over the course of RA therapy with a single daily oral dose (110 [Formula: see text]) of RA, reduced the peak thrombin levels and endogenous thrombin potential (ETP) up to 50 and 49%, respectively. We showed that progressive reductions in plasma levels of RA, observed in continuous RA therapy with a once-daily oral dose (110 [Formula: see text]) of RA, did not affect TM-mediated reduction of thrombin generation significantly. This finding prompts the hypothesis that continuous RA treatment has more consistent therapeutic effects on coagulation disorders than on cancer. CONCLUSIONS:Our results indicate that the oscillatory upregulation of TM expression on the endothelial cells over the course of RA therapy could potentially contribute to the treatment of coagulation abnormalities in cancer patients. Further studies on the impacts of RA therapy on the procoagulant activity of cancer cells are needed to better elucidate the mechanisms by which RA therapy improves hemostatic abnormalities in cancer.
Submitter of the first revision: Matthew Roberts
Submitter of this revision: Krishna Kumar Tiwari
Modellers: Matthew Roberts, Krishna Kumar Tiwari

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PubMed 30764845

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Mathematical Modelling Ontology differential equation model

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Model files

Ghaffari2019_TM_exp.xml SBML L2V4 file for TM expression and release model. PDPK model file in added under additional files 30.08 KB Preview | Download

Additional files

Ghaffari2019.cps Original file 60.05 KB Preview | Download
Ghaffari2019_RA_PDPK.cps COPASI 4.27(417) file for RA PDPK model 65.46 KB Preview | Download
Ghaffari2019_RA_PDPK.sedml SEDML file for RA PKPD model 4.27 KB Preview | Download
Ghaffari2019_RA_PDPK.xml SBML L2V4 file for RA PKPD model 47.14 KB Preview | Download
Ghaffari2019_TM_exp.cps COPASI 4.27(217) file TM expression 66.93 KB Preview | Download
Ghaffari2019_TM_exp.sedml SEDML file for TM expression 9.41 KB Preview | Download

  • Model originally submitted by : Matthew Roberts
  • Submitted: Jul 14, 2019 1:10:08 PM
  • Last Modified: Mar 16, 2020 5:48:19 PM
  • Version: 4 public model Download this version
    • Submitted on: Mar 16, 2020 5:48:19 PM
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Edited model metadata online.
  • Version: 2 public model Download this version
    • Submitted on: Jul 14, 2019 1:10:08 PM
    • Submitted by: Matthew Roberts
    • With comment: Edited model metadata online.

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