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Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived
Antiplatelet Therapies
#MMPMID28279968
Armstrong PC
; Hoefer T
; Knowles RB
; Tucker AT
; Hayman MA
; Ferreira PM
; Chan MV
; Warner TD
Arterioscler Thromb Vasc Biol
2017[May]; 37
(5
): 949-956
PMID28279968
show ga
OBJECTIVE: Aspirin together with thienopyridine P2Y(12) inhibitors, 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. APPROACH AND RESULTS:
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. CONCLUSIONS: 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.
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