title: Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies.
abstract: Aspirin together with thienopyridine P2Y12inhibitors, commonly clopidogrel, is a cornerstone of antiplatelet therapy. However, many patients receiving this therapy display high on-treatment platelet reactivity, which is a major therapeutic hurdle to the prevention of recurrent thrombotic events. The emergence of uninhibited platelets after thrombopoiesis has been proposed as a contributing factor to high on-treatment platelet reactivity. Here, we investigate the influences of platelet turnover on platelet aggregation in the face of different dual-antiplatelet therapy strategies.
  
  
  
  Traditional light transmission aggregometry, cytometry, advanced flow cytometric imaging, and confocal microscopy were used to follow the interactions of populations of platelets from healthy volunteers and patients with stable cardiovascular disease. Newly formed, reticulated platelets overproportionately contributed to, and clustered at, the core of forming aggregates. This phenomenon was particularly observed in samples from patients treated with aspirin plus a thienopyridine, but was absent in samples taken from patients treated with aspirin plus ticagrelor.
  
  
  
  Reticulated platelets are more reactive than older platelets and act as seeds for the formation of platelet aggregates even in the presence of antiplatelet therapy. This is coherent with the emergence of an uninhibited subpopulation of reticulated platelets during treatment with aspirin plus thienopyridine, explained by the short pharmacokinetic half-lives of these drugs. This phenomenon is absent during treatment with ticagrelor, because of its longer half-life and ability to act as a circulating inhibitor. These data highlight the important influences of pharmacokinetics on antiplatelet drug efficacies, especially in diseases associated with increased platelet turnover.
authors.affiliation: From The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom. p.c.armstrong@qmul.ac.uk.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Armstrong
authors.affiliation: From The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hoefer
authors.affiliation: From The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Knowles
authors.affiliation: From The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Tucker
authors.affiliation: From The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Hayman
authors.affiliation: From The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Plinio M
authors.initials: PM
authors.lastname: Ferreira
authors.affiliation: From The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Chan
authors.affiliation: From The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D058924:Thienopyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D034061:Thrombopoiesis; D000077486:Ticagrelor; D055815:Young Adult
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058924:Thienopyridines; D000077486:Ticagrelor; D000241:Adenosine; D001241:Aspirin
keywords: aspirin; blood platelets; platelet aggregation; thienopyridines; thrombosis