Key result
Factor Xa and thrombin increased ICAM-1 expression and MCP-1 secretion in endothelial cells, effects that were inhibited by vorapaxar and direct oral anticoagulants.
Why the study?
Factor Xa and thrombin exert non-hemostatic cellular actions primarily via PARs, but their effects and the effects of DOACs on OECs and HUVECs were unclear.
The inhibition of endothelial progenitor cell activation by vorapaxar and DOACs may represent a novel pleiotropic effect of these anticoagulants.
In vitro FXa/thrombin effects on endothelial ICAM-1 may not translate; leaves open DOAC modulation of non-hemostatic PAR signaling.
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.
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Papadaki et al. (2020) studied this question. Factor Xa, thrombin, and direct oral anticoagulants was evaluated on Membrane expression of ICAM-1 and secretion of MCP-1. Factor Xa and thrombin increased ICAM-1 expression and MCP-1 secretion in endothelial cells, effects that were inhibited by vorapaxar and direct oral anticoagulants.
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