Drug-Free Platelets Can Act as Seeds for Aggregate Formation During Antiplatelet Therapy.
Bottom Line: To model standard antiplatelet therapy, platelets were treated in vitro with aspirin, the P2Y12 receptor blocker prasugrel active metabolite, or aspirin plus prasugrel active metabolite.Light transmission aggregometry analysis demonstrated clear positive associations between proportions of drug-free platelets and percentage platelet aggregation in response to a range of platelet agonists.They demonstrate that a general population of platelets can contain subpopulations that respond strikingly differently to overall stimulation of the population and so act as the seed for platelet aggregation.
Affiliation: From The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom (T.H., P.C.A., M.F., M.V.C., T.D.W.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (N.S.K.).Show MeSH
Related in: MedlinePlus
Mentions: In summary, our studies shed new light on the responses recorded in many studies of ex vivo platelet reactivity and their association to antiplatelet drug therapy. Although it has previously been hypothesized that subpopulations of aspirin-free platelets act as individual generators of TXA2, we demonstrate for the first time a mechanism by which this is achieved; aspirin-free platelets are distributed throughout aspirin-inhibited platelet aggregates allowing generated TXA2 to activate a larger proportion of platelets (Figure 7). In contrast, platelets free of inhibition by irreversible P2Y12 receptor blockers, such as clopidogrel and prasugrel, form the core of platelet aggregates and act as the nexus for the formation of larger aggregates because P2Y12 receptor inhibited platelets are drawn in via other activation pathways. For DAPT, this leads to a complicated interaction between the ability of a minority of aspirin uninhibited platelets to drive a full TXA2-dependent response and a linear relationship between P2Y12 receptor blockade and platelet aggregation. Aggregatory responses, measured by LTA, have been associated with thrombotic risk and these have been linked to particular patient groups in which increased platelet turnover occurs.4,12–15 Our in vitro studies clearly indicate that such an increased ratio of drug-free platelets may be potentially critical to modulating thrombotic risk in conditions that are associated with increased platelet turnover, such as diabetes mellitus, chronic kidney disease, metabolic syndrome, and essential thrombocythemia. This is consistent with twice a day administration of aspirin providing an improved antiplatelet effect compared with standard once a day therapy in such patient groups.13,26,27,32,47 In essence, our studies indicate that in a patient receiving antiplatelet therapy in the form of either aspirin or DAPT consisting of aspirin plus a thienopyridine, a drug-free subpopulation can exist that will respond differently to platelet activators. This differential interaction and its potential to drive thrombosis are important both to consideration of individualized therapies and to the development of antiplatelet strategies.
Affiliation: From The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom (T.H., P.C.A., M.F., M.V.C., T.D.W.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (N.S.K.).