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Circulating MicroRNA Levels Indicate Platelet Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

1King's College London, King's British Heart Foundation Centre, London, United Kingdom, 2Health Research Institute La Fe, Valencia, Spain, 3University of Birmingham, Institute of Cardiovascular Sciences, Birmingham, United Kingdom, 4University of Sheffield, Department of Infection, Immunity and Cardiovascular Disease, Sheffield, United Kingdom, 5Medical University Innsbruck, Department of Neurology, Innsbruck, Austria, 6TAmiRNA GmbH, Vienna, Austria, 7Guy's and St Thomas' NHS Foundation Trust, Critical Care Medicine, London, United Kingdom, 8University of Leeds, Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds, United Kingdom

Abstract Number: PB0465

Meeting: ISTH 2020 Congress

Theme: Diagnostics and OMICs » Biomarkers of Thrombosis and Hemostasis

Background: There is emerging evidence for effects of platelet inhibition on innate immune activation. Levels of circulating microRNAs (miRNAs, miR) have been implicated as markers of platelet and immune cell activation. Here, we assess the effects of ticagrelor and clopidogrel on circulating miRNA levels during low dose endotoxemia.

Aims: To investigate whether miRNA levels can indicate platelet activation in endotoxemia despite platelet P2Y12 inhibition.

Methods: 30 healthy volunteers were randomly assigned to receive oral ticagrelor (n=10), clopidogrel (n=10) or no drug (n=10) for one week, followed by an intravenous bolus of 2ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 hours after endotoxin administration. 92 serum-miRNAs were screened using a custom-made LNA-based qPCR assay, followed by validation of 16 candidate miRNAs by TaqMan-qPCR (Figure 1).

[Figure 1]

Results:

  1. Levels of platelet-enriched miR-197, miR-223 and miR-223* were significantly lowerafter one week of antiplatelet therapy, whilst leukocyte-enriched miR-150 was not affected (Figure 2A).
  2. Endotoxin administration markedly reduced levels of leukocyte-enriched miR-150, whilst the opposite effect was seen for platelet-enriched miR-197, miR-223 and miR-223* (Figure 2B).
  3. Neither of these endotoxin-mediated effects on miRNAs were altered by P2Y12 inhibitors. MiRNA levels returned to baseline within 24 hours (Figure 2C).


[Figure 2]

Conclusions:

  1. Downregulation of miR-150 in response to endotoxin is in line with previous observations in critically ill sepsis patients, where miR-150 negatively correlates with survival.
  2. Circulating levels of platelet-associated miRNAs are responsive to antiplatelet therapy, but P2Y12 inhibitors fail to attenuate the rise of platelet miRNAs in response to low dose endotoxemia.
  3. Further studies in sepsis patients may reveal whether circulating miRNAs can aid the prediction of clinical outcomes.

Acknowledgements: C.G. is funded by a British Heart Foundation (BHF) PhD studentship. M.M. is a BHF Chair Holder (CH/16/3/32406) with BHF program grant support (RG/16/14/32397) and member of a network on “MicroRNA-based Therapeutic Strategies in Vascular Disease” funded by the Foundation Leducq. He is also supported by an excellent initiative (Competence Centers for Excellent Technologies [COMET]) of the FFG (Austrian Research Promotion Agency): Research Center of Excellence in Vascular Ageing-Tyrol, VASCage (K-Project No. 843536) funded by BMVIT (Federal Ministry for Transport, Innovation and Technology), BMWFW (federal Ministry of Science, Research and Economy), the Wirtschaftsagentur Wien, and Standortagentur Tirol.

To cite this abstract in AMA style:

Braza Boils* A, Barwari* T, Gutmann* C, Thomas MR, Judge HM, Joshi A, Pechlaner R, Skalicky S, Hackl M, Shankar-Hari M, Ajjan RA, Sabroe I, Storey RF, Mayr M, These three authors contributed equally to this work . Circulating MicroRNA Levels Indicate Platelet Activation in Endotoxemia Despite Platelet P2Y12 Inhibition [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/circulating-microrna-levels-indicate-platelet-activation-in-endotoxemia-despite-platelet-p2y12-inhibition/. Accessed September 27, 2023.

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