Aims: Haemostasis interrupts bleeding from disrupted blood vessels by activating platelet aggregation and coagulation. A similar mechanism termed thrombosis generates obstructive thrombi inside diseased arteries. As a consequence of this similarity, current anti-thrombotic agents increase the risk of bleeding. Atherosclerotic plaques produce significant amounts of prostaglandin E2 (PGE2), which activates its receptor EP3 on platelets and aggravates atherothrombosis. We investigated whether blocking EP3 could dissociate atherothrombosis from haemostasis.
Methods and results: Inhibiting in vivo the receptor EP3 for PGE2 with the blocking agent DG-041 reduced murine thrombosis triggered by local delivery of arachidonic acid or ferric chloride on healthy arteries. Importantly, it also reduced thrombosis triggered by scratching murine atherosclerotic plaques. PGE2 was not produced at the bleeding site after tail clipping. Consistently, blocking EP3 did not alter murine tail, liver, or cerebral haemostasis. Furthermore, blocking EP3 reduced murine pulmonary embolism and intensified platelet inhibition by clopidogrel leaving tail bleeding times unchanged. Human atherosclerotic plaques produced PGE2, which facilitated platelet aggregation in human blood and rescued the function of P2Y12-blocked platelets. Finally, in healthy patients, DG-041 reduced platelet aggregation, but did not significantly alter the cutaneous bleeding time at doses up to eight times the dose that inhibited the facilitating effect of PGE2 on platelets.
Conclusion: In mice, blocking EP3 inhibited atherothrombosis without affecting haemostasis and intensified efficiency of conventional anti-platelet treatment without aggravating the bleeding risk. In patients, blocking EP3 should improve the prevention of cardiovascular diseases, which is currently limited by the risk of bleeding.
Keywords: Anti-platelet agents; Atherothrombosis; Haemostasis; Prostaglandins.