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DOI: 10.1055/s-0043-1773763
Reticulated Platelets Predict Cardiovascular Death and Adverse Events in Coronary Artery Disease: A Systematic Review and Meta-analysis
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Abstract
Background The pro-thrombotic immature or reticulated platelets (RPs) are known to be elevated in high-risk patients and in different pathological settings. It has been shown that RPs correlate with an insufficient antiplatelet response to antiplatelet agents. RPs are emerging novel predictors of adverse cardiovascular events in cardiovascular disease. This study, using the totality of existing evidence, evaluated the prognostic role of RPs in patients with coronary artery disease.
Methods We performed a systematic review and meta-analysis including trials of acute and chronic coronary syndrome reporting clinical outcomes according to RPs levels in the peripheral blood. We compared patients with elevated RPs (RPshigh) to patients without elevated RPs (RPslow). Odds ratios (ORs) and 95% CIs were used as metric of choice for treatment effects with random-effects models. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE). Secondary endpoints were cardiovascular death, myocardial infarction, ischemic stroke, urgent coronary revascularization and bleedings.
Results A total of 7 studies, including 2213 patients, were included. The risk for MACCE was significantly higher in RPshigh compared to RPslow patients (OR 2.67 [1.87; 3.81], I2 = 43.8%). RPshigh were associated with cardiovascular death (OR 2.09 [1.36; 3.22], I2 = 40.4%). No associations for RPshigh were detected with the other singular components of MACCE: myocardial infarction (OR 1.73 [0.89; 3.38] I2 = 60.5%) and stroke (OR 1.72 [0.59; 4.96] I2 = 21%). The risk of bleeding did not differ between groups(OR 0.58 [0.15; 2.22] I2 = 86.1%).
Conclusion Elevated RPs are significantly associated with increased risk of cardiovascular events and cardiovascular death.
Key Words
ACS - immature platelets - immature platelet fraction - IPF - reticulated platelets - CCS - biomarker* These authors contributed equally to this study.
Publication History
Received: 21 April 2023
Accepted: 31 July 2023
Article published online:
11 September 2023
© 2023. Thieme. All rights reserved.
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References
- 1 Bongiovanni D, Han J, Klug M. et al. Role of reticulated platelets in cardiovascular disease. Arterioscler Thromb Vasc Biol 2022; 42 (05) 527-539
- 2 Cesari F, Marcucci R, Gori AM. et al. Reticulated platelets predict cardiovascular death in acute coronary syndrome patients. Insights from the AMI-Florence 2 study. Thromb Haemost 2013; 109 (05) 846-853
- 3 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 (20) 2122-2129
- 4 Freynhofer MK, Iliev L, Bruno V. et al. Platelet turnover predicts outcome after coronary intervention. Thromb Haemost 2017; 117 (05) 923-933
- 5 López-Jiménez RA, Martín-Herrero F, González-Porras JR, Sánchez-Barba M, Martín-Luengo C, Pabón-Osuna P. Immature platelet fraction: a new prognostic marker in acute coronary syndrome. Rev Esp Cardiol (Engl Ed) 2013; 66 (02) 147-148
- 6 Perl L, Matatov Y, Koronowski R, Lev EI, Solodky A. Prognostic significance of reticulated platelet levels in diabetic patients with stable coronary artery disease. Platelets 2020; 31 (08) 1012-1018
- 7 Tscharre M, Farhan S, Bruno V. et al. Impact of platelet turnover on long-term adverse cardiovascular outcomes in patients undergoing percutaneous coronary intervention. Eur J Clin Invest 2019; 49 (09) e13157
- 8 Bongiovanni D, Schreiner N, Gosetti R. et al. Immature platelet fraction predicts adverse events in patients with acute coronary syndrome: the ISAR-REACT 5 reticulated platelet substudy. Arterioscler Thromb Vasc Biol 2023; 43 (02) e83-e89
- 9 Anetsberger A, Blobner M, Haller B. et al. Immature platelets as a novel biomarker for adverse cardiovascular events in patients after non-cardiac surgery. Thromb Haemost 2017; 117 (10) 1887-1895
- 10 Imperiali CE, Lopez-Delgado JC, Dastis-Arias M, Sanchez-Navarro L. Evaluation of the delta of immature platelet fraction as a predictive biomarker of inflammatory response after cardiac surgery. J Clin Pathol 2020; 73 (06) 335-340
- 11 Bongiovanni D, Santamaria G, Klug M. et al. Transcriptome analysis of reticulated platelets reveals a prothrombotic profile. Thromb Haemost 2019; 119 (11) 1795-1806
- 12 Hille L, Lenz M, Vlachos A. et al. Ultrastructural, transcriptional, and functional differences between human reticulated and non-reticulated platelets. J Thromb Haemost 2020; 18 (08) 2034-2046
- 13 Petzold T, Zhang Z, Ballesteros I. et al. Neutrophil “plucking” on megakaryocytes drives platelet production and boosts cardiovascular disease. Immunity 2022; 55 (12) 2285.e7-2299.e7
- 14 Bernlochner I, Klug M, Larasati D. et al. Sorting and magnetic-based isolation of reticulated platelets from peripheral blood. Platelets 2021; 32 (01) 113-119
- 15 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372 (71) n71
- 16 Stroup DF, Berlin JA, Morton SC. et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283 (15) 2008-2012
- 17 Sterne JA, Hernán MA, Reeves BC. et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016; 355: i4919
- 18 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7 (03) 177-188
- 19 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414) 557-560
- 20 Lin L, Chu H. Quantifying publication bias in meta-analysis. Biometrics 2018; 74 (03) 785-794
- 21 Denis MM, Tolley ND, Bunting M. et al. Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 2005; 122 (03) 379-391
- 22 Bigalke B, Lindemann S, Ehlers R. et al. Expression of platelet collagen receptor glycoprotein VI is associated with acute coronary syndrome. Eur Heart J 2006; 27 (18) 2165-2169
- 23 Italiano Jr JE, Richardson JL, Patel-Hett S. et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet α granules and differentially released. Blood 2008; 111 (03) 1227-1233
- 24 van Nispen tot Pannerden H, de Haas F, Geerts W, Posthuma G, van Dijk S, Heijnen HF. The platelet interior revisited: electron tomography reveals tubular α-granule subtypes. Blood 2010; 116 (07) 1147-1156
- 25 Bendall SC, Nolan GP, Roederer M, Chattopadhyay PK. A deep profiler's guide to cytometry. Trends Immunol 2012; 33 (07) 323-332
- 26 Blair TA, Michelson AD, Frelinger III AL. Mass cytometry reveals distinct platelet subtypes in healthy subjects and novel alterations in surface glycoproteins in glanzmann thrombasthenia. Sci Rep 2018; 8 (01) 10300
- 27 Mills EW, Green R, Ingolia NT. Slowed decay of mRNAs enhances platelet specific translation. Blood 2017; 129 (17) e38-e48
- 28 Cecchetti L, Tolley ND, Michetti N, Bury L, Weyrich AS, Gresele P. Megakaryocytes differentially sort mRNAs for matrix metalloproteinases and their inhibitors into platelets: a mechanism for regulating synthetic events. Blood 2011; 118 (07) 1903-1911
- 29 Stratz C, Nührenberg T, Amann M. et al. Impact of reticulated platelets on antiplatelet response to thienopyridines is independent of platelet turnover. Thromb Haemost 2016; 116 (05) 941-948
- 30 Bernlochner I, Goedel A, Plischke C. et al. Impact of immature platelets on platelet response to ticagrelor and prasugrel in patients with acute coronary syndrome. Eur Heart J 2015; 36 (45) 3202-3210
- 31 Zhao Y, Lai R, Zhang Y, Shi D. The prognostic value of reticulated platelets in patients with coronary artery disease: a systematic review and meta-analysis. Front Cardiovasc Med 2020; 7: 578041
- 32 Watanabe K, Takeuchi K, Kawai Y, Ikeda Y, Kubota F, Nakamoto H. Automated measurement of reticulated platelets in estimating thrombopoiesis. Eur J Haematol 1995; 54 (03) 163-171
- 33 Abe Y, Wada H, Tomatsu H. et al. A simple technique to determine thrombopoiesis level using immature platelet fraction (IPF). Thromb Res 2006; 118 (04) 463-469