Anti-platelet drugs and their necessary interaction with endothelial mediators and platelet cyclic nucleotides for therapeutic efficacy.

For many millions of patients at secondary risk of coronary thrombosis pharmaceutical protection is supplied by dual anti-platelet therapy. Despite substantial therapeutic developments over the last decade recurrent thrombotic events occur, highlighting the need for further optimisation of therapies. Importantly, but often ignored, anti-platelet drugs interact with cyclic nucleotide systems in platelets and these are the same systems that mediate key endogenous pathways of platelet regulation, notably those dependent upon the vascular endothelium. The aim of this review is to highlight interactions between the anti-platelet drugs, aspirin and P2Y12 receptor antagonists and endogenous pathways of platelet regulation at the level of cyclic nucleotides. These considerations are key to concepts such as anti-platelet drug resistance and individualized anti-platelet therapy which cannot be understood by study of platelets in isolation from the circulatory environment. We also explore novel and emerging therapies that focus on preserving haemostasis and how the concepts outlined in this review could be exploited therapeutically to improve anti-thrombotic efficacy whilst reducing bleeding risk.