Legacy of blood: does prasugrel inhibit megakaryocytes and do juvenile platelets inherit this inhibition?

Abstract

A cute coronary syndromes (ACS) are the first cause of death in the Western world. ACS are caused by a ruptured atherosclerotic plaque on the coronary arteries with the formation of a superimposed thrombus which occludes coronary circulation.1 Although novel therapies for atherosclerosis are under study, 2 since the establishment of the role of platelets in ACS pathogenesis, platelet inhibition remains the cornerstone of medical therapy for ACS. The P2Y 12 receptor inhibitor prasugrel has been demonstrated to reduce recurrent ischemic events in ACS patients. Thienopyridines (clopidogrel and prasugrel) are prodrugs requiring biotransformation into an active metabolite. As thienopyridines irreversibly bind and antagonize the P2Y 12 receptor for the entire platelet lifespan, the formation of new platelets is required to recover platelet function. The clinical implications of this pharmacological effect are obvious; the slow offset of the antiplatelet effect due to this irreversible P2Y 12 receptor inhibition may be potentially problematic in the management of patients who are treated before coronary angiography and then require coronary artery bypass graft surgery or who need other unanticipated surgical procedures or who experiment severe bleeding. Given that we do not have a complete understanding of the offset period after discontinuation of thienopyridines, Baaten et al. 4 aimed to investigate the dynamics of platelet functional recovery after prasugrel cessation.Megakaryocytes in the vascular niche of the bone marrow generate platelets by extending long filaments or pseudopods termed proplatelets which protrude through the vascular endothelium into the sinusoid lumen, where platelets, stemming from the proplatelet tips, are released into the bloodstream. Juvenile or immature platelets (also termed reticulated platelets because the presence of mRNA produces a reticulated pattern after staining with thiazole orange very similar to erythroid reticulocytes) represent the youngest component of the circulating platelet pool in animals (less than 24 h old).5 Juvenile platelets exhibit larger volume, a greater number of dense granules, and more aggregation/reactivity than older circulating platelets. This increased thrombotic potential seems to be due to their content of cytosolic mRNA that is translationally active, which enables the expression of ADP receptors and prothrombotic factors. The number of juvenile platelets inversely correlates with responsiveness to clopidogrel 6 and prasugrel, 7 and also predicts adverse cardiovascular prognosis and future ACS. 8 Whether levels of juvenile platelets are a marker of risk or a risk factor 9 for ACS has still not been clarified. In their present manuscript, Baaten et al.4 studied 16 STEMI patients on aspirin and prasugrel, who suspended prasugrel after one year. The authors first confirmed that P2Y 12 -inhibited platelets participate less in thrombosis. Second, the authors showed that ADP-induced platelet aggregation (both using light-transmission aggregometry and th...

Possible roles of platelet-derived microparticles in atherosclerosis

“…They can also be derived directly from the megakaryocytes, but these microparticles may have less contribution to inflammation and complement activation, which differs from microparticles derived from activated platelets [9,10]. And the drug prasugrel can not only inhibit circulating platelets but act directly on megakaryocytes, thus leading to the inhibition of juvenile platelets and MP released by megakacyocytes, and hence create a "blood legacy" [11]. PMPs are distinguished from exsomes derived from endocytosis and released from multivesicular endosomes.…”