Download PDF
Semin Thromb Hemost 2022; 48(05): 542-551
DOI: 10.1055/s-0042-1742742
Review Article

Flow Cytometric Assessment of Changes in Platelet Reactivity after Acute Coronary Syndrome: A Systematic Review

Oliver Buchhave Pedersen
1   Thrombosis and Hemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Leonardo Pasalic
4   Institute of Clinical Pathology and Medical Research, Departments of Clinical and Laboratory Hematology, Westmead University Hospital, Sydney, Australia
,
Peter H. Nissen
1   Thrombosis and Hemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Erik Lerkevang Grove
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Steen Dalby Kristensen
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Anne-Mette Hvas
1   Thrombosis and Hemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
› Author Affiliations Funding The authors received financial support from Department of Clinical Biochemistry, Aarhus University Hospital.
› Further Information
    Permissions and Reprints

Abstract

Increased platelet activity is an important predictor for recurrent cardiovascular events in patients with acute coronary syndromes (ACS). Flow cytometry is an advanced method for evaluation of platelet activity. We aimed to summarize the current literature on dynamic changes in platelet activity analyzed by flow cytometry in patients with ACS. Employing the guidelines of Preferred Report Items for Systematic Reviews and Meta-Analyses (PRISMA), we searched PubMed and Embase on October 26, 2021, and identified studies measuring platelet activity with flow cytometry in ACS patients in the acute phase (baseline) and at follow-up in a more stable phase. In the 12 included studies, fibrinogen receptor, α-granule secretion, platelet reactivity index, monocyte-platelet aggregates, neutrophil-platelet aggregates, and reticulated platelets were measured. The fibrinogen receptor and α-granule secretion were either unchanged or lower during follow-up measurements than in the acute phase. Platelet reactivity index showed inconsistent results. Values of monocyte-platelet aggregates and neutrophil-platelet aggregates were lower at follow-up than at baseline (p-values <0.05). Reticulated platelets were either unchanged (p-value >0.64) or lower at 1 to 2 months follow-up (p-value 0.04), and also lower at 5 months to 1-year follow-up (p-value >0.005) compared with baseline. Overall, flow cytometric analyses of platelet function in ACS patients showed that platelet activity was lower at follow-up than at baseline. However, in some patients, platelet activity remained unchanged from baseline to follow-up, possibly indicating a sustained high platelet activity that may increase the risk of recurrent cardiovascular events.

Keywords

flow cytometry - platelet function tests - platelet activation - acute coronary syndromes

Supplementary Material



Publication History

Article published online:
28 February 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Ibanez B, James S, Agewall S. et al; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018; 39 (02) 119-177
    CrossrefPubMedGoogle Scholar
  • 2 Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J 2015; 36 (19) 1163-1170
    CrossrefPubMedGoogle Scholar
  • 3 Alenazy FO, Thomas MR. Novel antiplatelet targets in the treatment of acute coronary syndromes. Platelets 2021; 32 (01) 15-28
    CrossrefPubMedGoogle Scholar
  • 4 Aradi D, Sibbing D, Bonello L. Current evidence for monitoring platelet reactivity in acute coronary syndrome: a plea for individualized antiplatelet treatment. Int J Cardiol 2013; 167 (05) 1794-1797
    CrossrefPubMedGoogle Scholar
  • 5 Martin JF, Kristensen SD, Mathur A, Grove EL, Choudry FA. The causal role of megakaryocyte–platelet hyperactivity in acute coronary syndromes. Nat Rev Cardiol 2012; 9 (11) 658-670
    CrossrefPubMedGoogle Scholar
  • 6 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109 (25) 3171-3175
    CrossrefPubMedGoogle Scholar
  • 7 Lordkipanidzé M. Platelet function tests. Semin Thromb Hemost 2016; 42 (03) 258-267
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Hvas AM, Grove EL. Platelet function tests: preanalytical variables, clinical utility, advantages, and disadvantages. Methods Mol Biol 2017; 1646: 305-320
    CrossrefPubMedGoogle Scholar
  • 9 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Ramström S, Södergren AL, Tynngård N, Lindahl TL. Platelet function determined by flow cytometry: new perspectives?. Semin Thromb Hemost 2016; 42 (03) 268-281
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Pedersen OH, Nissen PH, Hvas AM. Platelet function investigation by flow cytometry: sample volume, needle size, and reference intervals. Platelets 2018; 29 (02) 199-202
    CrossrefPubMedGoogle Scholar
  • 12 Rubak P, Nissen PH, Kristensen SD, Hvas AM. Investigation of platelet function and platelet disorders using flow cytometry. Platelets 2016; 27 (01) 66-74
    CrossrefPubMedGoogle Scholar
  • 13 Pedersen OH, Larsen ML, Grove EL. et al. Platelet characteristics in patients with essential thrombocytosis. Cytometry B Clin Cytom 2018; 94 (06) 918-927
    CrossrefPubMedGoogle Scholar
  • 14 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
    CrossrefPubMedGoogle Scholar
  • 15 The National Heart LaBIotNIoH. Study quality assessment tools. Accessed November 9, 2021 at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools.2013
    PubMedGoogle Scholar
  • 16 Koziński M, Obońska K, Stankowska K. et al. Prasugrel overcomes high on-clopidogrel platelet reactivity in the acute phase of acute coronary syndrome and maintains its antiplatelet potency at 30-day follow-up. Cardiol J 2014; 21 (05) 547-556
    CrossrefPubMedGoogle Scholar
  • 17 Aurigemma C, Scalone G, Tomai F. et al. Persistent enhanced platelet activation in patients with acute myocardial infarction and coronary microvascular obstruction: clinical implications. Thromb Haemost 2014; 111 (01) 122-130
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Eisen A, Lerman-Shivek H, Perl L. et al. Circulating reticulated platelets over time in patients with myocardial infarction treated with prasugrel or ticagrelor. J Thromb Thrombolysis 2015; 40 (01) 70-75
    CrossrefPubMedGoogle Scholar
  • 19 Kalantzi KI, Dimitriou AA, Goudevenos JA, Tselepis AD. The platelet hyporesponsiveness to clopidogrel in acute coronary syndrome patients treated with 75 mg/day clopidogrel may be overcome within 1 month of treatment. Platelets 2012; 23 (02) 121-131
    CrossrefPubMedGoogle Scholar
  • 20 Murasaki S, Murasaki K, Tanoue K, Kawana M, Hagiwara N, Kasanuki H. Circulating platelet and neutrophil activation correlates with the clinical course of unstable angina. Heart Vessels 2007; 22 (06) 376-382
    CrossrefPubMedGoogle Scholar
  • 21 Perl L, Lerman-Shivek H, Rechavia E. et al. Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2014; 63 (06) 513-517
    CrossrefPubMedGoogle Scholar
  • 22 Storey RF, Kotha J, Smyth SS. et al. Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy. Thromb Haemost 2014; 111 (05) 883-891
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Vaduganathan M, Zemer-Wassercug N, Rechavia E. et al. Relation between ticagrelor response and levels of circulating reticulated platelets in patients with non-ST elevation acute coronary syndromes. J Thromb Thrombolysis 2015; 40 (02) 211-217
    CrossrefPubMedGoogle Scholar
  • 24 Yip HK, Wu CJ, Hang CL. et al. Serial changes in platelet activation in patients with unstable angina following coronary stenting: evaluation of the effects of clopidogrel loading dose in inhibiting platelet activation. Circ J 2005; 69 (10) 1208-1211
    CrossrefPubMedGoogle Scholar
  • 25 Gawaz M, Neumann FJ, Ott I, May A, Schömig A. Platelet activation and coronary stent implantation. Effect of antithrombotic therapy. Circulation 1996; 94 (03) 279-285
    CrossrefPubMedGoogle Scholar
  • 26 Ferreiro JL, Vivas D, De La Hera JM. et al. High and low on-treatment platelet reactivity to P2Y12 inhibitors in a contemporary cohort of acute coronary syndrome patients undergoing percutaneous coronary intervention. Thromb Res 2019; 175: 95-101
    CrossrefPubMedGoogle Scholar
  • 27 Fedor M, Samoš M, Šimonová R. et al. Monitoring the efficacy of ADP inhibitor treatment in patients with acute STEMI post-PCI by VASP-P flow cytometry assay. Clin Appl Thromb Hemost 2015; 21 (04) 334-338
    CrossrefPubMedGoogle Scholar
  • 28 Jortveit J, Halvorsen S, Kaldal A, Pripp AH, Govatsmark RES, Langørgen J. Unsatisfactory risk factor control and high rate of new cardiovascular events in patients with myocardial infarction and prior coronary artery disease. BMC Cardiovasc Disord 2019; 19 (01) 71
    CrossrefPubMedGoogle Scholar
  • 29 Bonello L, Pansieri M, Mancini J. et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol 2011; 58 (05) 467-473
    CrossrefPubMedGoogle Scholar
  • 30 Udell JA, Bonaca MP, Collet JP. et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J 2016; 37 (04) 390-399
    PubMedGoogle Scholar
  • 31 Wiviott SD, Braunwald E, McCabe CH. et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20) 2001-2015
    CrossrefPubMedGoogle Scholar
  • 32 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
    PubMedGoogle Scholar
  • 33 Faber J, Hvas AM, Kristensen SD, Grove EL, Adelborg K. Immature platelets and risk of cardiovascular events among patients with ischemic heart disease: a systematic review. Thromb Haemost 2021; 121 (05) 659-675
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Monaco C, Mathur A, Martin JF. What causes acute coronary syndromes? Applying Koch's postulates. Atherosclerosis 2005; 179 (01) 1-15
    CrossrefPubMedGoogle Scholar
  • 35 Khan SU, Singh M, Valavoor S. et al. Dual antiplatelet therapy after percutaneous coronary intervention and drug-eluting stents: a systematic review and network meta-analysis. Circulation 2020; 142 (15) 1425-1436
    CrossrefPubMedGoogle Scholar
  • 36 Mehran R, Baber U, Sharma SK. et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med 2019; 381 (21) 2032-2042
    CrossrefPubMedGoogle Scholar
  • 37 Angiolillo DJ, Been L, Rubinstein M, Martin M, Rollini F, Franchi F. Use of the VerifyNow point of care assay to assess the pharmacodynamic effects of loading and maintenance dose regimens of prasugrel and ticagrelor. J Thromb Thrombolysis 2021; 51 (03) 741-747
    CrossrefPubMedGoogle Scholar
  • 38 Michelson AD, Barnard MR, Krueger LA, Frelinger III AL, Furman MI. Evaluation of platelet function by flow cytometry. Methods 2000; 21 (03) 259-270
    CrossrefPubMedGoogle Scholar