. 2023 Sep 29;14:1244098. doi: 10.3389/fphar.2023.1244098

TABLE 5.

Overview of the pleiotropic effects of DOACs in endothelial cells (ECs) in vitro.

Endothelial cell type	DOACs dose	Stimulation factor	Physiological effects	Biological/Pleiotropic effects	Reference
OECs and HUVECs	Dabigatran (0,1–20 μM), Rivaroxaban (0,1–20 μM)	Thrombin (80 nM) or FXa (50 nM)	↓ ICAM1 membrane expression	Anti-inflammatory effects	Papadaki et al. (2020)
OECs and HUVECs	Dabigatran (0,1–20 μM), Rivaroxaban (0,1–20 μM)	Thrombin (80 nM) or FXa (50 nM)	↓ CCL2 secretion	Anti-inflammatory effects	Papadaki et al. (2020)
HUVECs	Rivaroxaban (0,1–3 μM)	Thrombin (10 nM)	↓ SELE, ICAM1, VCAM1, IL-8, CCL2, CXCL1, CXCL2, TF	Anti-inflammatory effects	Ellinghaus et al. (2016)
	Dabigatran (0,1–3 μM)		↓ SELE, ICAM1, VCAM1, IL-8, CCL2, CXCL1, CXCL2, TF	Anti-inflammatory effects
	Dabigatran (10–30 nM)		↑CXCL1, CXCL2, IL-8, SELE, CCL2, TF	Pro-inflammatory effect
HUVECs	Dabigatran (160, 800 nM), Rivaroxaban (230, 1150 nM)	25-hydroxycholesterol (25 μM)	↑ TGFB1, IL-37	Anti-inflammatory effects	Gorzelak-Pabiś et al. (2022b)
			↓ IL-18, IL-23, and IL-35	Anti-inflammatory effects	Gorzelak-Pabiś et al. (2022b)
			Repair DNA single-strand breaks	Protect from DNA damage	Woźniak et al. (2020)
			↓ ROS generation	Anti-oxidant effects	Woźniak et al. (2020)
HBEC-5i + Human Astrocytes	Dabigatran (500 nM), Rivaroxaban (500 nM), Apixaban (500 nM)	Thrombin (100 nM)	↓ Permeability, PAR-1 cleavage	Stabilizes BBB integrity and anti-hemorrhagic effects	Puech et al. (2019)
HBEC-5i + Human Astrocytes		Thrombin (100 nM)	↑TJP1, CDH5 expression	Stabilizes BBB integrity and anti-hemorrhagic effects	Puech et al. (2019)
EA.hy926	Dabigatran (200 nM)	Anti-TM, Anti-EPCR, Anti-APC	Non-APC signaling activation	Non- APC mediating bleeding	von Drygalski et al. (2020)
EA.hy926	Rivaroxaban (200 nM), Apixaban (200 nM), Edoxaban (200 nM)	Anti-TM, Anti-EPCR, Anti-APC	APC signaling activation	APC mediating bleeding	von Drygalski et al. (2020)

OECs, Outgrowth Endothelial Cells; HUVECs, Human Umbilical Vein Endothelial Cells; HBEC-5i, Human Brain Endothelial Cells-5 immortalized; EA.hy926, Immortalized Human Umbilical Vein Endothelial Cell Line; TM, Thrombomodulin; EPCR, Endothelial Protein C Receptor; APC, Activated Protein C; ICAM1, Intercellular Adhesion Molecule-1; CCL2, C-C Motif Chemokine Ligand 2; SELE, Selectin E; VCAM, Vascular Cell Adhesion Molecule; IL-8, Interleukin 8; CXCL2, C-X-C Motif Chemokine 2; TF, Tissue Factor; TGFB1, Transforming Growth Factor Beta 1; ROS, Reactive Oxygen Species; PAR, Proteinase-Activated Receptor; TJP1, Tight Junction Protein 1; CDH5, Cadherin 5.