Abstract
Islet and hepatocyte transplantation are associated with tissue factor-dependent activation of coagulation which elicits instant blood mediated inflammatory reaction, thereby contributing to a low rate of engraftment. The aim of this study was i) to evaluate the procoagulant activity of human adult liver-derived mesenchymal progenitor cells (hALPCs), ii) to compare it to other mesenchymal cells of extra-hepatic (bone marrow mesenchymal stem cells and skin fibroblasts) or liver origin (liver myofibroblasts), and iii) to determine the ways this activity could be modulated. Using a whole blood coagulation test (thromboelastometry), we demonstrated that all analyzed cell types exhibit procoagulant activity. The hALPCs pronounced procoagulant activity was associated with an increased tissue factor and a decreased tissue factor pathway inhibitor expression as compared with hepatocytes. At therapeutic doses, the procoagulant effect of hALPCs was inhibited by neither antithrombin activators nor direct factor Xa inhibitor or direct thrombin inhibitors individually. However, concomitant administration of an antithrombin activator or direct factor Xa inhibitor and direct thrombin inhibitor proved to be a particularly effective combination for controlling the procoagulant effects of hALPCs both in vitro and in vivo. The results suggest that this dual antithrombotic therapy should also improve the efficacy of cell transplantation in humans.
Highlights
Adult mesenchymal stem/progenitor cells are currently under evaluation in several clinical trials
One limitation is the finding that isolated hepatocytes exhibit procoagulant activity (PCA), which was found to be linked to tissue factor (TF) expression
This in vitro observation has been found to translate clinically in modifications in coagulation parameters and D-dimer levels in recipients of liver cell transplantation, which is suggestive of infraclinical microthrombotic events [8].The TF dependent PCA of hepatocytes has more recently been confirmed by an independent team which reported that all the parameters of the instant blood mediated inflammatory reaction (IBMIR) were documented in a tubing loop model, whole blood coagulation model mimicking blood circulation [9]
Summary
Adult mesenchymal stem/progenitor cells are currently under evaluation in several clinical trials. One limitation is the finding that isolated hepatocytes exhibit procoagulant activity (PCA), which was found to be linked to tissue factor (TF) expression. This in vitro observation has been found to translate clinically in modifications in coagulation parameters and D-dimer levels in recipients of liver cell transplantation, which is suggestive of infraclinical microthrombotic events [8].The TF dependent PCA of hepatocytes has more recently been confirmed by an independent team which reported that all the parameters of the instant blood mediated inflammatory reaction (IBMIR) were documented in a tubing loop model, whole blood coagulation model mimicking blood circulation [9]. PCA led to thrombotic events, and elicited inflammatory reactions involving the up-regulation of adhesion molecule expression and chemokine production, two critical pathways affecting graft success rate [10,11,12,13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
