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Thromb Haemost 2023; 123(02): 231-244
DOI: 10.1055/s-0042-1758655
Blood Cells, Inflammation and Infection

P2Y12 Inhibition Suppresses Proinflammatory Platelet–Monocyte Interactions

Christina C. Rolling 
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
2   Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Marcin A. Sowa
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
,
Tricia T. Wang
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
,
MacIntosh Cornwell 
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
,
Khrystyna Myndzar
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
,
Tamar Schwartz
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
,
Hanane El Bannoudi
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
,
Jill Buyon
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
,
Tessa J. Barrett‡   *
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
,
Jeffrey S. Berger‡   *
1   Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States
› Author Affiliations Funding This study was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant no. RO 6121 1/1 to C.C.R. and the National Heart, Lung, and Blood Institute of the National Institutes of Health (R35HL144993 to J.S.B and R01HL139909 to J.B. and J.S.B).
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Abstract

Background Monocyte–platelet aggregates (MPAs) represent the crossroads between thrombosis and inflammation, and targeting this axis may suppress thromboinflammation. While antiplatelet therapy (APT) reduces platelet–platelet aggregation and thrombosis, its effects on MPA and platelet effector properties on monocytes are uncertain.

Objectives To analyze the effect of platelets on monocyte activation and APT on MPA and platelet-induced monocyte activation.

Methods Agonist-stimulated whole blood was incubated in the presence of P-selectin, PSGL1, PAR1, P2Y12, GP IIb/IIIa, and COX-1 inhibitors and assessed for platelet and monocyte activity via flow cytometry. RNA-Seq of monocytes incubated with platelets was used to identify platelet-induced monocyte transcripts and was validated by RT-qPCR in monocyte-PR co-incubation ± APT.

Results Consistent with a proinflammatory platelet effector role, MPAs were increased in patients with COVID-19. RNA-Seq revealed a thromboinflammatory monocyte transcriptome upon incubation with platelets. Monocytes aggregated to platelets expressed higher CD40 and tissue factor than monocytes without platelets (p < 0.05 for each). Inhibition with P-selectin (85% reduction) and PSGL1 (87% reduction) led to a robust decrease in MPA. P2Y12 and PAR1 inhibition lowered MPA formation (30 and 21% reduction, p < 0.05, respectively) and decreased monocyte CD40 and TF expression, while GP IIb/IIIa and COX1 inhibition had no effect. Pretreatment of platelets with P2Y12 inhibitors reduced the expression of platelet-mediated monocyte transcription of proinflammatory SOCS3 and OSM.

Conclusions Platelets skew monocytes toward a proinflammatory phenotype. Among traditional APTs, P2Y12 inhibition attenuates platelet-induced monocyte activation.

Keywords

aspirin - monocytes - antiplatelet therapy - platelet activation - thromboinflammation

Author Contributions

The study was conceived by C.C.R., T.J.B., and J.S.B. Experiments were performed by C.C.R., M.A.S., T.T.W., K.M., T.S., and H.E.B. Data analysis, interpretation, and visualization were conducted by C.C.R., M.C., T.J.B., and J.S.B. The first version of the manuscript was drafted by C.C.R. and critically revised and edited by T.J.B. and J.S.B. All co-authors reviewed and edited the manuscript.


* These authors contributed equally.


Supplementary Material



Publication History

Received: 09 May 2022

Accepted: 23 September 2022

Article published online:
11 January 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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