Pleiotropic effects of NOACs with focus on edoxaban: scientific findings and potential clinical implications

Figures

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  Fig. 1. Role of thrombin and factor Xa in haemostasis. Activation of factor Xa and thrombin (IIa) as key players in haemostasis ultimately results in the formation of cross-linked fibrin clots. Main physiological activator of the coagulation cascade is tissue factor. TF tissue factor

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  Fig. 2. The role of protease-activated receptors in atherosclerosis. Factor Xa and thrombin induce activation of the protease-activated receptors PAR‑1 and PAR‑2 on endothelial cells, vascular smooth muscle cells, and macrophages. Increased inflammation, proliferation, cell adhesion and migration are the consequence, resulting in the development and progression of atherosclerosis

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  Fig. 3. Potential targets for pleiotropic effects of edoxaban in vivo. Translational view from the in vitro and animal experiments described in this review to the human organ systems which might potentially be affected by the pleiotropic effects of factor Xa inhibition

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  Fig. 4. a Total number of AF episodes and b total length of AF episodes after treatment of C57/B6J wildtype mice with vehicle (0.5% methylcellulose; Ctr, n = 8), angiotensin II (1.5 ng/g/min for 2 weeks via osmotic minipump; AngII, n = 8), or angiotensin II plus edoxaban (1.5 ng/g/min for 2 weeks via osmotic minipump; edoxaban 0.25 mg/mouse/day in 0.5% methylcellulose orally; AngII + Edo, n = 10). An AF episode was defined as a series of repetitive atrial ectopic beats lasting for more than 1 s. *p < 0.05. AF atrial fibrillation, AngII angiotensin II, Ctr control, Edo edoxaban

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  Fig. 5. a Histochemical evaluation of atrial fibrosis by picrosirius red staining (Ctr, n = 6; AngII, n = 9; AngII+Edo, n = 15). b Atrial collagen I expression relative to Ctr as indicated by immunoblotting. (Ctr, n = 6; AngII, n = 6; AngII + Edo, n = 6). *p < 0.05. c Total PAR‑2 expression and d cleavage (activation) of PAR‑2 as indicated by immunoblotting of control, angiotensin II- or angiotensin II + edoxaban-treated animals (Ctr, n = 5; AngII, n = 5; AngII + Edo, n = 5). No significant differences were detected. C57/B6J wildtype mice treated with vehicle (0.5% methylcellulose; Ctr), angiotensin II (1.5 ng/g/min for 2 weeks via osmotic minipump; AngII), or angiotensin II plus edoxaban (1.5 ng/g/min for 2 weeks via osmotic minipump; edoxaban 0.25 mg/mouse/day in 0.5% methylcellulose orally; AngII + Edo). AngII angiotensin II, Ctr control, Edo edoxaban

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  Fig. 6. Dot blot array intensity analysis of pooled plasma from Ctr, AngII or AngII + Edo- treated mice (n = 6 for all groups), normalised to cytokine levels of Ctr (100%, left panel). Yellow asterisks: AngII + Edo vs. Ctr; grey asterisks: AngII + Edo vs. AngII; *p < 0.05, **p < 0.01, **p < 0.001. AngII angiotensin II, Ctr control, Edo edoxaban