Introduction Endogenous endothelial vasodilators and ticagrelor both vasodilate and inhibit platelets. This study evaluated a potential mechanistic interaction between ticagrelor and endothelial vasodilators in patients with stable coronary disease.

Methods Participants were assessed at baseline and after 3 days of ticagrelor. Blood samples were incubated with nitric oxide (GSNO) donor or prostacyclin (PGI₂) and then maximally activated. Using flow cytometry, P-selectin, VASP phosphorylation (-P) and platelet leukocyte aggregate (PLA) associated fluorescence were quantified as measures of platelet activation. EndoPAT measured endothelial function (reactive hyperaemic index (RHI)).

Results Sixty-three patients were included. There was a synergistic relationship between ticagrelor and both vasodilators (GSNO and PGI₂) (Figure). VASP-P, as evidence of signalling, was significantly increased in platelets post ticagrelor. PLA results were consistent and showed a greater response to prostacyclin after ticagrelor. RHI increased post ticagrelor (1.91 to 2.04 p=0.049). The magnitude of RHI increase positively correlated to the extent of platelet inhibition by ticagrelor (p=0.014).

Conclusion P2Y₁₂ inhibition by ticagrelor enhances the antiplatelet effects of endothelial vasodilators and endothelial function. The extent of endothelial improvement can predict the anti-platelet response to ticagrelor.

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Abstract 3 Figure 1

Evidence of synergism between endothelial vasodilators and ticagrelor following platelet activation (PAR1 agonist 10 µM). A: histogram demonstrating the percentage of platelet inhibition in whole blood (WB) with increasing concentrations of PGI2 and in platelet rich plasma with increasing concentrations of GSNO. Significantly greater inhibition of p-selection expression was seen following ticagrelor, statistically beyond the expected additive effect B: histogram of VASP phosphorylation associated fluorescence (median fluorescence intensity) fold change from unstimulated baseline in response to PGI₂. No effect demonstrated by ticagrelor alone but a statistically greater fold change seen in response to PGI₂post ticagrelor administration C: dose response curve to PGI₂ showing percentage formation of platelet leukocyte aggregates. No significant difference seen in the absence of PGI₂ however an important reduction in percentage post ticagrelor with the addition of PGI₂.All measurements at baseline (solid bar/black line) and post three days of ticagrelor (open bar/grey line). Error bars to one standard deviation. **p value<0.001; *p value<0.003