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Review
. 2023 May 15:10:960398.
doi: 10.3389/fcvm.2023.960398. eCollection 2023.

Platelet-monocyte aggregates: molecular mediators of thromboinflammation

Christina C Rolling  1   2 , Tessa J Barrett  1 , Jeffrey S Berger  1
Affiliations
Review

Platelet-monocyte aggregates: molecular mediators of thromboinflammation

Christina C Rolling et al. Front Cardiovasc Med. .

Abstract

Platelets, key facilitators of primary hemostasis and thrombosis, have emerged as crucial cellular mediators of innate immunity and inflammation. Exemplified by their ability to alter the phenotype and function of monocytes, activated platelets bind to circulating monocytes to form monocyte-platelet aggregates (MPA). The platelet-monocyte axis has emerged as a key mechanism connecting thrombosis and inflammation. MPA are elevated across the spectrum of inflammatory and autoimmune disorders, including cardiovascular disease, systemic lupus erythematosus (SLE), and COVID-19, and are positively associated with disease severity. These clinical disorders are all characterized by an increased risk of thromboembolic complications. Intriguingly, monocytes in contact with platelets become proinflammatory and procoagulant, highlighting that this interaction is a central element of thromboinflammation.

Keywords: P2Y12 inhibitor; antiplatelet therapy; atherosclerosis; inflammatory diseases; monocyte-platelet aggregates; thromboinflammation.

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Conflict of interest statement

Jeffrey Berger is PI for the NIH-funded ACTIV4a trial investigating P2Y12 inhibitors in patients hospitalized with COVID-19. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Platelets interact with circulating monocytes by direct attachment onto the monocyte surface, by release of alpha and dense granules containing chemokines and cytokines, and by shedding of microvesicles. Monocytes in turn upregulate inflammation markers on their surface, overexpress proinflammatory transcripts, secrete chemokines and cytokines, show enhanced migration potential, and differentiate into proinflammatory macrophages. Created with BioRender.com
Figure 2
Figure 2
Schematic overview of potential therapeutic targets to prevent monocyte-platelet interactions. Depicted are G protein-coupled receptors (GPCR) associated with platelet receptors P2Y12 and PAR1 as well as GPIIb/IIIa receptors on the platelet surface, and cyclooxygenase-1 (COX-1)-mediated production of platelet-activating thromboxane A2. Following platelet activation, many interconnected pathways result in intracellular calcium increase, activation of GPIIb/IIIa, and release of alpha and dense granule contents. P-selectin (released from alpha granules) translocates to the platelet surface and binds to P-selectin glycoprotein ligand-1 (PSGL1) on the monocyte surface, resulting in monocyte-platelet aggregates (MPA). In turn, monocytes become proinflammatory and procoagulant. *has received a conditional marketing authorization by the European Medicines Agency in 2020. Figure created with BioRender.com
Figure 3
Figure 3
Visual summary on the role of MPA in cardiovascular disease. Plasma levels of circulating monocyte-platelet aggregates are increased in inflammatory diseases. Platelet-induced proinflammatory monocytes secrete inflammatory cytokines and chemokines (1), attach to and activate endothelial cells (2), show enhanced transendothelial migration potential (3), and differentiate into proinflammatory macrophages that contribute to the progression of atherosclerosis. Figure created with BioRender.com
See this image and copyright information in PMC

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