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

Abstract

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 ) 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 ) 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 ) 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.

RNA-Sequencing, Connectivity Mapping, and Molecular Docking to Investigate Ligand-Protein Binding for Potential Drug Candidates for the Treatment of Wilms Tumor

“…Retinoic acid is the bioactive metabolite of Vitamin A, which is a compound that potentially prevents or treats malignancy and which participates in multiple biological processes [29,30]. Retinoic acid can suppress the growth of cancer cells in vitro and induces cell death in breast cancer, neuroblastoma, gastric carcinoma, prostate cancer, pancreatic cancer, and acute promyelocytic leukemia cells [31][32][33]. In 2005, molecular studies showed that the trans-retinoic acid gene (ATRA) had the potential for the treatment for Wilms tumor.…”

Combined FOLFOX4 with all-trans retinoic acid versus FOLFOX4 with placebo in treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a randomized, double-blind comparative study

“…For example, coagulation abnormalities in high-risk patients with APL treated with ATRA were shown to be amenable to treatment via suppression of intrinsic mechanisms that accelerated extracellular chromatin degradation. 30 Hamed et al 31 reported that ATRA, by upregulating thrombomodulin (TM) expression on the surfaces of endothelial cells and causing oscillatory elevation of TM expression on endothelial cells during ATRA treatment, played a role in the treatment of coagulation disorders in cancer patients. All these studies demonstrated that ATRA targeted and affected the coagulation cascade reaction.…”

Advances in Computational Fluid Mechanics in Cellular Flow Manipulation: A Review

“…Moreover, microfluidic devices have been proposed to study the possible effects of microbubbles in microvessels [28] to represent the effects of these bubbles, which can form in the blood vessels occasionally and cause possible pathological events, such as preventing the food to reach to the cells in specific regions. Also, targeted drug delivery via nanomaterials, such as carbon nanotubes, was introduced recently and significantly increased the efficacy of the drugs [31][32][33][34]. As evaluation of these particles are highly dependent on their microenvironments, finding the optimum design point is facing some difficulties [35] and microfluidic systems can offer exceptional abilities to screen the nanoparticles to resolve these difficulties [1].…”