Factor Xa and thrombin induce endothelial progenitor cell activation. The effect of direct oral anticoagulants

Abstract

Factor Xa (FXa) and thrombin exert non-hemostatic cellular actions primarily mediated through protease-activated receptors (PARs). We investigated the effect of FXa and thrombin on human late-outgrowth endothelial cells (OECs), a type of endothelial progenitor cells (EPCs), and on human umbilical vein endothelial cells (HUVECs). The effect of direct oral anticoagulants (DOACs), rivaroxaban and dabigatran, was also studied. The membrane expression of intercellular adhesion molecule-1 (ICAM-1) and the secretion of monocyte chemoattractant protein-1 (MCP-1) were used as cell activation markers. FXa and thrombin increase the ICAM-1 expression and the MCP-1 secretion on both cells, being higher on OECs. Vorapaxar, a specific PAR-1 antagonist, completely inhibits FXa-induced activation of both cells and thrombin-induced HUVEC activation, but only partially thrombin-induced OEC activation. Furthermore, thrombin-receptor activating peptide; TRAP-6, only partially activates OECs. OECs do not membrane-express PAR-4, therefore it may not be involved on thrombin-induced OEC activation. Rivaroxaban and dabigatran inhibit OEC and HUVEC activation by FXa and thrombin, respectively. Rivaroxaban enhances thrombin-induced OEC and HUVEC activation, which is completely inhibited by vorapaxar. The inhibition of OEC and HUVEC activation by vorapaxar and DOACs may represent a new pleiotropic effect of these drugs. The pathophysiological and clinical significance of our findings need to be established.

Keywords:

• Dabigatran
• endothelial progenitor cells
• Factor Xa
• rivaroxaban
• thrombin
• vorapaxar

Acknowledgements

The authors thank the Atherothrombosis Research Centre of the University of Ioannina for providing access to the laboratory equipment and facilities. The authors also thank the Department of Obstetrics and Gynecology, School of Medicine of the University of Ioannina for kindly providing OECs.

Authors’ Contribution

Styliani Papadaki, Sofia Sidiropoulou and Iraklis C. Moschonas performed all the experiments. Styliani Papadaki analyzed the data and wrote the draft of the manuscript. Alexandros D. Tselepis conceived the present study, coordinated the study and wrote the manuscript.

Disclosure of Interest

The authors report no conflict of interest.

Additional information

Funding

The present research has been co-financed by the Operational Program “Human Resources Development, Education and Lifelong Learning” and is co-financed by the European Union (European Social Fund) and Greek national funds [grant number (MIS) 5006031].