MicroRNA as Biomarkers for Platelet Function and Maturity in Patients with Cardiovascular Disease

Oliver Buchhave Pedersen; Erik Lerkevang Grove; Steen Dalby Kristensen; Peter H. Nissen; Anne-Mette Hvas

doi:10.1055/s-0041-1730375

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2022; 122(02): 181-195
DOI: 10.1055/s-0041-1730375

Review Article

MicroRNA as Biomarkers for Platelet Function and Maturity in Patients with Cardiovascular Disease

Authors

Oliver Buchhave Pedersen

¹Department of Clinical Biochemistry, Thrombosis and Haemostasis Research Unit, Aarhus University Hospital, Aarhus, Denmark

²Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
Erik Lerkevang Grove

²Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

³Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
Steen Dalby Kristensen

²Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

³Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
Peter H. Nissen

¹Department of Clinical Biochemistry, Thrombosis and Haemostasis Research Unit, Aarhus University Hospital, Aarhus, Denmark

³Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
Anne-Mette Hvas

¹Department of Clinical Biochemistry, Thrombosis and Haemostasis Research Unit, Aarhus University Hospital, Aarhus, Denmark

³Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark

Abstract

Patients with cardiovascular disease (CVD) are at increased risk of suffering myocardial infarction. Platelets are key players in thrombus formation and, therefore, antiplatelet therapy is crucial in the treatment and prevention of CVD. MicroRNAs (miRs) may hold the potential as biomarkers for platelet function and maturity. This systematic review was conducted using the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). To identify studies investigating the association between miRs and platelet function and maturity in patients with CVD, PubMed and Embase were searched on October 13 and December 13, 2020 without time boundaries. Risk of bias was evaluated using a standardized quality assessment tool. Of the 16 included studies, 6 studies were rated “good” and 10 studies were rated “fair.” In total, 45 miRs correlated significantly with platelet function or maturity (rho ranging from –0.68 to 0.38, all p < 0.05) or differed significantly between patients with high platelet reactivity and patients with low platelet reactivity (p-values ranging from 0.0001 to 0.05). Only four miRs were investigated in more than two studies, namely miR-223, miR-126, miR-21 and miR-150. Only one study reported on the association between miRs and platelet maturity. In conclusion, a total of 45 miRs were associated with platelet function or maturity in patients with CVD, with miR-223 and miR-126 being the most frequently investigated. However, the majority of the miRs were only investigated in one study. More data are needed on the potential use of miRs as biomarkers for platelet function and maturity in CVD patients.

Keywords

MicroRNAs - biomarker - platelet function test - prognosis - cardiovascular disease

Full Text

References

References
1 WHO. Cardiovascular diseases (CVDs). 2020 . Available at: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
2 Sjögren M, Almgren P, Melander O. Polygenetic risk for coronary artery disease increases hospitalization burden and mortality. Int J Cardiol Heart Vasc 2019; 24: 100391
3 Adelborg K, Grove EL, Sundbøll J, Laursen M, Schmidt M. Sixteen-year nationwide trends in antithrombotic drug use in Denmark and its correlation with landmark studies. Heart 2016; 102 (23) 1883-1889
4 Freynhofer MK, Bruno V, Wojta J, Huber K. The role of platelets in athero-thrombotic events. Curr Pharm Des 2012; 18 (33) 5197-5214
5 Grove EL, Würtz M, Thomas MR, Kristensen SD. Antiplatelet therapy in acute coronary syndromes. Expert Opin Pharmacother 2015; 16 (14) 2133-2147
6 Gremmel T, Frelinger III AL, Michelson AD. Platelet physiology. Semin Thromb Hemost 2016; 42 (03) 191-204
7 Halvorsen S, Andreotti F, ten Berg JM. et al. Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis. J Am Coll Cardiol 2014; 64 (03) 319-327
8 Patrono C, Morais J, Baigent C. et al. Antiplatelet agents for the treatment and prevention of coronary atherothrombosis. J Am Coll Cardiol 2017; 70 (14) 1760-1776
9 Schrör K. Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemost 1997; 23 (04) 349-356
10 Larsen SB, Grove EL, Neergaard-Petersen S, Würtz M, Hvas AM, Kristensen SD. Determinants of reduced antiplatelet effect of aspirin in patients with stable coronary artery disease. PLoS One 2015; 10 (05) e0126767
11 Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med 2007; 167 (15) 1593-1599
12 Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ 2008; 336 (7637): 195-198
13 Guirgis M, Thompson P, Jansen S. Review of aspirin and clopidogrel resistance in peripheral arterial disease. J Vasc Surg 2017; 66 (05) 1576-1586
14 Rocca B, Dragani A, Pagliaccia F. Identifying determinants of variability to tailor aspirin therapy. Expert Rev Cardiovasc Ther 2013; 11 (03) 365-379
15 Würtz M, Grove EL. Interindividual variability in the efficacy of oral antiplatelet drugs: definitions, mechanisms and clinical importance. Curr Pharm Des 2012; 18 (33) 5344-5361
16 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 (03) 459-468
17 Cesari F, Marcucci R, Caporale R. et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 2008; 99 (05) 930-935
18 Guthikonda S, Alviar CL, Vaduganathan M. et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 2008; 52 (09) 743-749
19 McBane II RD, Gonzalez C, Hodge DO, Wysokinski WE. Propensity for young reticulated platelet recruitment into arterial thrombi. J Thromb Thrombolysis 2014; 37 (02) 148-154
20 Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature 2008; 455 (7209): 64-71
21 Arroyo AB, de Los Reyes-García AM, Teruel-Montoya R, Vicente V, González-Conejero R, Martínez C. microRNAs in the haemostatic system: more than witnesses of thromboembolic diseases?. Thromb Res 2018; 166: 1-9
22 Lim LP, Lau NC, Garrett-Engele P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433 (7027): 769-773
23 Rowley JW, Schwertz H, Weyrich AS. Platelet mRNA: the meaning behind the message. Curr Opin Hematol 2012; 19 (05) 385-391
24 Lu J, Guo S, Ebert BL. et al. MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Dev Cell 2008; 14 (06) 843-853
25 Girardot M, Pecquet C, Boukour S. et al. miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets. Blood 2010; 116 (03) 437-445
26 Tran JQD, Pedersen OH, Larsen ML. et al. Platelet microRNA expression and association with platelet maturity and function in patients with essential thrombocythemia. Platelets 2020; 31 (03) 365-372
27 Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol 2009; 16 (09) 961-966
28 Liberati A, Altman DG, Tetzlaff J. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009; 6 (07) e1000100
29 Martin JF, Trowbridge EA, Salmon G, Plumb J. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983; 32 (05) 443-460
30 The National Heart LaBIotNIoH. Study Quality Assessment Tools. 2013 . Available at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
31 Li L, Wu F, Xie Y. et al. MiR-202-3p inhibits foam cell formation and is associated with coronary heart disease risk in a Chinese population. Int Heart J 2020; 61 (01) 153-159
32 Xie W, Yin Q, Zhang M, Li S, Chen S. Leukocyte miR-223-3p is not associated with altered platelet responses to clopidogrel in patients with coronary artery disease. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018; 43 (04) 421-427
33 Becker KC, Kwee LC, Neely ML. et al. Circulating MicroRNA profiling in non-ST elevated coronary artery syndrome highlights genomic associations with serial platelet reactivity measurements. Sci Rep 2020; 10 (01) 6169
34 Li S, Guo LZ, Kim MH, Han JY, Serebruany V. Platelet microRNA for predicting acute myocardial infarction. J Thromb Thrombolysis 2017; 44 (04) 556-564
35 Binderup HG, Houlind K, Madsen JS, Brasen CL. Aspirin resistance may be identified by miR-92a in plasma combined with platelet distribution width. Clin Biochem 2016; 49 (15) 1167-1172
36 Chen S, Qi X, Chen H. et al. Expression of miRNA-26a in platelets is associated with clopidogrel resistance following coronary stenting. Exp Ther Med 2016; 12 (01) 518-524
37 Chen YC, Lin FY, Lin YW. et al. Platelet MicroRNA 365-3p expression correlates with high on-treatment platelet reactivity in coronary artery disease patients. Cardiovasc Drugs Ther 2019; 33 (02) 129-137
38 Chyrchel B, Totoń-Żurańska J, Kruszelnicka O. et al. Association of plasma miR-223 and platelet reactivity in patients with coronary artery disease on dual antiplatelet therapy: A preliminary report. Platelets 2015; 26 (06) 593-597
39 Ding T, Zeng X, Cheng B. et al. Platelets in acute coronary syndrome patients with high platelet reactivity after dual antiplatelet therapy exhibit upregulation of miR-204-5p. Ann Clin Lab Sci 2019; 49 (05) 619-631
40 Jäger B, Stojkovic S, Haller PM. et al. Course of platelet miRNAs after cessation of P2Y12 antagonists. Eur J Clin Invest 2019; 49 (08) e13149
41 Kaudewitz D, Skroblin P, Bender LH. et al. Association of MicroRNAs and YRNAs with platelet function. Circ Res 2016; 118 (03) 420-432
42 Shi R, Ge L, Zhou X. et al. Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity. Thromb Res 2013; 131 (06) 508-513
43 Peng L, Liu J, Qin L. et al. Interaction between platelet-derived microRNAs and CYP2C19*2 genotype on clopidogrel antiplatelet responsiveness in patients with ACS. Thromb Res 2017; 157: 97-102
44 Tang QJ, Lei HP, Wu H. et al. Plasma miR-142 predicts major adverse cardiovascular events as an intermediate biomarker of dual antiplatelet therapy. Acta Pharmacol Sin 2019; 40 (02) 208-215
45 Zhang YY, Zhou X, Ji WJ. et al. Decreased circulating microRNA-223 level predicts high on-treatment platelet reactivity in patients with troponin-negative non-ST elevation acute coronary syndrome. J Thromb Thrombolysis 2014; 38 (01) 65-72
46 Zufferey A, Ibberson M, Reny JL. et al. New molecular insights into modulation of platelet reactivity in aspirin-treated patients using a network-based approach. Hum Genet 2016; 135 (04) 403-414
47 Faraldi M, Gomarasca M, Sansoni V, Perego S, Banfi G, Lombardi G. Normalization strategies differently affect circulating miRNA profile associated with the training status. Sci Rep 2019; 9 (01) 1584
48 Fejes Z, Póliska S, Czimmerer Z. et al. Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus. Thromb Haemost 2017; 117 (03) 529-542
49 Singh S, de Ronde MWJ, Kok MGM. et al. MiR-223-3p and miR-122-5p as circulating biomarkers for plaque instability. Open Heart 2020; 7 (01) e001223
50 Pan Y, Liang H, Liu H. et al. Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via targeting the insulin-like growth factor 1 receptor. J Immunol 2014; 192 (01) 437-446
51 Kaur A, Mackin ST, Schlosser K. et al. Systematic review of microRNA biomarkers in acute coronary syndrome and stable coronary artery disease. Cardiovasc Res 2020; 116 (06) 1113-1124
52 Kahner BN, Shankar H, Murugappan S, Prasad GL, Kunapuli SP. Nucleotide receptor signaling in platelets. J Thromb Haemost 2006; 4 (11) 2317-2326
53 Wang S, Aurora AB, Johnson BA. et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell 2008; 15 (02) 261-271
54 Fish JE, Santoro MM, Morton SU. et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 2008; 15 (02) 272-284
55 Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A 2008; 105 (05) 1516-1521
56 Meng Q, Wang W, Yu X. et al. Upregulation of MicroRNA-126 contributes to endothelial progenitor cell function in deep vein thrombosis via its target PIK3R2. J Cell Biochem 2015; 116 (08) 1613-1623
57 Jansen F, Yang X, Hoelscher M. et al. Endothelial microparticle-mediated transfer of MicroRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles. Circulation 2013; 128 (18) 2026-2038
58 Schober A, Nazari-Jahantigh M, Wei Y. et al. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med 2014; 20 (04) 368-376
59 Dai B, Wang F, Nie X. et al. The cell type-specific functions of miR-21 in cardiovascular diseases. Front Genet 2020; 11: 563166
60 Raitoharju E, Oksala N, Lehtimäki T. MicroRNAs in the atherosclerotic plaque. Clin Chem 2013; 59 (12) 1708-1721
61 Weber M, Baker MB, Moore JP, Searles CD. MiR-21 is induced in endothelial cells by shear stress and modulates apoptosis and eNOS activity. Biochem Biophys Res Commun 2010; 393 (04) 643-648
62 Suárez Y, Fernández-Hernando C, Pober JS, Sessa WC. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 2007; 100 (08) 1164-1173
63 Ji R, Cheng Y, Yue J. et al. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res 2007; 100 (11) 1579-1588
64 Tano N, Kim HW, Ashraf M. microRNA-150 regulates mobilization and migration of bone marrow-derived mononuclear cells by targeting Cxcr4. PLoS One 2011; 6 (10) e23114
65 Murphy AJ, Bijl N, Yvan-Charvet L. et al. Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis. Nat Med 2013; 19 (05) 586-594
66 Farina NH, Wood ME, Perrapato SD. et al. Standardizing analysis of circulating microRNA: clinical and biological relevance. J Cell Biochem 2014; 115 (05) 805-811
67 Zampetaki A, Mayr M. Analytical challenges and technical limitations in assessing circulating miRNAs. Thromb Haemost 2012; 108 (04) 592-598
68 Willeit P, Zampetaki A, Dudek K. et al. Circulating microRNAs as novel biomarkers for platelet activation. Circ Res 2013; 112 (04) 595-600
69 Kaudewitz D, Lee R, Willeit P. et al. Impact of intravenous heparin on quantification of circulating microRNAs in patients with coronary artery disease. Thromb Haemost 2013; 110 (03) 609-615
70 Gidlöf O, Andersson P, van der Pals J, Götberg M, Erlinge D. Cardiospecific microRNA plasma levels correlate with troponin and cardiac function in patients with ST elevation myocardial infarction, are selectively dependent on renal elimination, and can be detected in urine samples. Cardiology 2011; 118 (04) 217-226
71 Willeit P, Skroblin P, Moschen AR. et al. Circulating MicroRNA-122 Is associated with the risk of new-onset metabolic syndrome and type 2 diabetes. Diabetes 2017; 66 (02) 347-357
72 Boeckel JN, Thomé CE, Leistner D, Zeiher AM, Fichtlscherer S, Dimmeler S. Heparin selectively affects the quantification of microRNAs in human blood samples. Clin Chem 2013; 59 (07) 1125-1127
73 Grove EL, Hvas AM, Johnsen HL. et al. A comparison of platelet function tests and thromboxane metabolites to evaluate aspirin response in healthy individuals and patients with coronary artery disease. Thromb Haemost 2010; 103 (06) 1245-1253

Supplementary Material

Supplementary Material (PDF)