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Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients

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...

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Autores principales: Ghaffari, Hamed, Varner, Jeffrey D., Petzold, Linda R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376718/
https://www.ncbi.nlm.nih.gov/pubmed/30764845
http://dx.doi.org/10.1186/s12976-019-0099-z
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author Ghaffari, Hamed
Varner, Jeffrey D.
Petzold, Linda R.
author_facet Ghaffari, Hamed
Varner, Jeffrey D.
Petzold, Linda R.
author_sort Ghaffari, Hamed
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12976-019-0099-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-63767182019-02-27 Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients Ghaffari, Hamed Varner, Jeffrey D. Petzold, Linda R. Theor Biol Med Model Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12976-019-0099-z) contains supplementary material, which is available to authorized users. BioMed Central 2019-02-14 /pmc/articles/PMC6376718/ /pubmed/30764845 http://dx.doi.org/10.1186/s12976-019-0099-z Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Ghaffari, Hamed
Varner, Jeffrey D.
Petzold, Linda R.
Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients
title Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients
title_full Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients
title_fullStr Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients
title_full_unstemmed Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients
title_short Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients
title_sort analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376718/
https://www.ncbi.nlm.nih.gov/pubmed/30764845
http://dx.doi.org/10.1186/s12976-019-0099-z
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