In 2019, Knowles and Warner [70] hypothesized that a synergistic ability of P2Y12 blockade and endothelial mediators, PGI2 and NO (and their intraplatelet second messengers, cyclic adenosine 3’,5’-monophosphate (cAMP) and cyclic guanosine 3’,5’-monophosphate (cGMP), respectively) to inhibit platelet aggregation [30, 32, 71] might be of particular clinical relevance in post-ACS subjects with the above mentioned comorbidities, sharing widespread endothelial dysfunction and chronic inflammatory activation. Here, P2RY12 is linked to endothelial dysfunction.