Immature Platelets
2016; Lippincott Williams & Wilkins; Volume: 134; Issue: 14 Linguagem: Inglês
10.1161/circulationaha.116.022538
ISSN1524-4539
Autores Tópico(s)Coronary Interventions and Diagnostics
ResumoHomeCirculationVol. 134, No. 14Immature Platelets Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBImmature PlateletsClinical Relevance and Research Perspectives Eli I. Lev, MD Eli I. LevEli I. Lev From Rabin Medical Center, Tel-Aviv University, Israel. Originally published4 Oct 2016https://doi.org/10.1161/CIRCULATIONAHA.116.022538Circulation. 2016;134:987–988IntroductionSince the recognition that platelets have an essential role in the pathogenesis of acute coronary syndromes (ACS) and other thrombotic disorders, extensive research has been devoted to understanding platelet physiology and to the development of effective antiplatelet therapy. For several decades, it has been known that the circulating platelet population is heterogeneous in size and age. This population includes young platelets, recently released from the bone marrow by megakaryocytes, which are termed reticulated platelets (RPs). Circulating RPs are identified by staining for messenger ribonucleic acid (mRNA). They are characterized by increased mean volume and a greater number of dense granules than older circulating platelets, and a capacity for ongoing protein synthesis by the residual mRNA. The proportion of RPs in the circulation is increased in situations of enhanced platelet turnover, including ACS. However, it is not clear whether, in ACS, enhanced platelet turnover is the cause or the consequence of the acute atherothrombotic event.The proportion of RPs in the circulation is generally assessed by flow cytometry using thiazole orange staining of mRNA. This method, however, has several limitations. It is relatively expensive and technically demanding, and it lacks standardization of the type and concentration of dye used. For these reasons, a simpler automated method has been developed for quantification of immature platelets. This laboratory method is performed in a fully automated blood analyzer with optical fluorescence capability (eg, Sysmex XE-2100). Platelet mRNA is stained in the autoanalyzer with 2 fluorescent dyes, and cell volume and mRNA content are measured to identify younger platelets. Results are expressed as immature platelet fraction (IPF). Reports have shown good correlation between RP levels (measured by flow cytometry) and IPF. Furthermore, IPF measurement can be incorporated into a complete blood count test with relatively little additional cost.Research of immature platelets has recently focused on 2 main areas: the effect of this platelet population on response to antiplatelet drugs, and the potential association with clinical outcomes in patients with cardiovascular disease. Numerous studies have shown that there is significant interindividual variability in the pharmacodynamic response to aspirin and clopidogrel and, to a much lesser extent, prasugrel and ticagrelor. Furthermore, hyporesponse to these drugs, reflected by high on-treatment platelet reactivity, has been clearly associated with adverse ischemic events. Because RPs are believed to be more prothrombotic and hyperreactive than mature platelets,1 a higher proportion of RPs could be associated with attenuated response to antiplatelet drugs. In patients with stable coronary artery disease treated with aspirin and clopidogrel, a higher proportion of RPs strongly correlated with reduced response to both drugs, a finding confirmed by subsequent studies in other patient populations.2 We have recently shown that a higher proportion of circulating RPs also correlates strongly with reduced response to prasugrel in patients with acute myocardial infarction.3 This finding has been confirmed by using IPF to quantify immature platelets.1 In contrast with the association between RP levels and response to prasugrel, no significant association was found between RPs and ticagrelor.1,2The mechanism underlying the association between circulating RPs and attenuated response to several antiplatelet drugs may be related to a number of factors. First, a higher proportion of RPs reflects an enhanced rate in which new platelets are released to the circulation. These new platelets are only affected to a limited degree by irreversible antiplatelet drugs with a short plasma half-life (eg, aspirin, 2–6 hours; and the active metabolite of clopidogrel, ≈8 hours), which are mostly bound to older platelets. In contrast, ticagrelor is a reversibly binding drug that can dissociate from older platelets and bind to newly released platelets. Furthermore, the twice-daily dosing of ticagrelor together with a plasma half-life of ≈12 hours increases drug exposure and inhibition of newly released platelets. Other factors that may explain the association between RPs and response to antiplatelet drugs are the characteristics of platelet hyperreactivity (eg, increased P-selectin expression),1 and residual mRNA content that may enable increased expression of adenosine diphosphate receptors and prothrombotic and proinflammatory proteins.Despite the growing evidence associating enhanced platelet turnover with insufficient platelet inhibition in response to antiplatelet drugs, data are limited regarding the clinical significance of immature platelets. Mean platelet volume, an index of platelet size, and, therefore, an indirect marker of immature platelets, has been associated with adverse ischemic events, including cardiovascular mortality in patients with ACS or following coronary intervention. Two recent studies have directly examined the association between immature platelets, expressed as IPF, and clinical outcomes.4,5 These studies, which consisted of ≈100 to 200 patients with ACS or stable coronary artery disease, have shown that IPF is an independent predictor of major adverse cardiovascular events, including cardiovascular death.Further research is required to understand the mechanism by which immature platelets affect response to antiplatelet drugs and to better characterize their association with clinical outcomes. Investigation of the surface antigenic characteristics of this platelet population, and the signals that regulate platelet turnover, size, and reactivity, is essential for developing more effective antiplatelet therapy. In addition, larger clinical studies are required to demonstrate the predictive and prognostic value of this novel biomarker for adverse cardiovascular events. Preliminary data have shown that indices of platelet turnover may have stronger clinical predictive value than platelet function tests.2 Measurement of RPs, or the more readily available IPF, may allow for better risk stratification of patients with ACS. In addition, measurement of platelet turnover markers may allow for individualized antiplatelet therapy (guided by RP or IPF levels). Patients with enhanced platelet turnover may benefit more from reversibly binding drugs with longer half-lives, and twice-daily dosing (eg, ticagrelor), or twice-daily dosing regimens of drugs with shorter pharmacokinetic half-lives. To this end, there is growing interest in twice-daily dosing of aspirin in patients with diabetes mellitus, known to have larger and more reactive platelets with shorter platelet life spans. Thus, although circulating immature platelets, as a marker of platelet turnover, were identified decades ago, their continued study offers a unique opportunity to improve antiplatelet therapeutic strategies in patients with cardiovascular disease.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the Editors or of the American Heart Association.Circulation is available at http://circ.ahajournals.org.Correspondence to: Eli I. Lev, MD, Rabin Medical Center, Jabotinsky St, Petah-Tikva, Tel-Aviv University, Israel. E-mail [email protected]References1. Bernlochner I, Goedel A, Plischke C, Schüpke S, Haller B, Schulz C, Mayer K, Morath T, Braun S, Schunkert H, Siess W, Kastrati A, Laugwitz KL. Impact of immature platelets on platelet response to ticagrelor and prasugrel in patients with acute coronary syndrome.Eur Heart J. 2015; 36:3202–3210. doi: 10.1093/eurheartj/ehv326.CrossrefMedlineGoogle Scholar2. Freynhofer MK, Gruber SC, Grove EL, Weiss TW, Wojta J, Huber K. Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing.Thromb Haemost. 2015; 114:459–468. doi: 10.1160/TH15-02-0179.CrossrefMedlineGoogle Scholar3. Perl L, Lerman-Shivek H, Rechavia E, Vaduganathan M, Leshem-Lev D, Zemer-Wassercug N, Dadush O, Codner P, Bental T, Battler A, Kornowski R, Lev EI. Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction.J Am Coll Cardiol. 2014; 63:513–517. doi: 10.1016/j.jacc.2013.07.110.CrossrefMedlineGoogle Scholar4. Cesari F, Marcucci R, Gori AM, Caporale R, Fanelli A, Casola G, Balzi D, Barchielli A, Valente S, Giglioli C, Gensini GF, Abbate R. Reticulated platelets predict cardiovascular death in acute coronary syndrome patients. Insights from the AMI-Florence 2 Study.Thromb Haemost. 2013; 109:846–853. doi: 10.1160/TH12-09-0709.CrossrefMedlineGoogle Scholar5. Ibrahim H, Schutt RC, Hannawi B, DeLao T, Barker CM, Kleiman NS. Association of immature platelets with adverse cardiovascular outcomes.J Am Coll Cardiol. 2014; 64:2122–2129. doi: 10.1016/j.jacc.2014.06.1210.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Jiang L, Ji J, Ge P, Zhu T, Mi Q, Tai T, Li Y and Xie H (2021) Is platelet responsiveness to clopidogrel attenuated in overweight or obese patients and why? A reverse translational study in mice, British Journal of Pharmacology, 10.1111/bph.15667, 179:1, (46-64), Online publication date: 1-Jan-2022. Cohen A, Harari E, Cipok M, Laish-Farkash A, Bryk G, Yahud E, Sela Y, Lador N, Mann T, Mayo A and Lev E (2020) Immature platelets in patients hospitalized with Covid-19, Journal of Thrombosis and Thrombolysis, 10.1007/s11239-020-02290-6, 51:3, (608-616), Online publication date: 1-Apr-2021. 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