Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19
<p>Main inflammatory mediators of platelet activation. (<b>A</b>) Endothelial dysfunction in the setting of inflammation results in increased platelet–endothelial cell interactions, thinning of endothelial glycocalyx, and reduced nitric oxide bioavailability, contributing to platelet activation. (<b>B</b>) Neutrophil-derived molecules and extracellular vesicles aid platelet activation, together with the pro-thrombotic role of NET histones via a Toll-like receptor 4-related platelet activation. (<b>C</b>) Platelet toll-like receptors cannot directly induce platelet activation but they augment it, stimulated by NF-κB, thromboxane, adenosine diphosphate, and adenosine triphosphate. (<b>D</b>) Pro-inflammatory interleukins bind to interleukin receptors situated on the platelet surface while tumor necrosis factor-alpha promotes alterations in bone marrow, inflammation, and mitochondria, collectively facilitating platelet activation. ADAMTS13: A disintegrin-like and metalloprotease with thrombospondin type-1 repeats-13, NO: nitric oxide, EC: endothelial cells, eGC: endothelial glycocalyx, cGMP: cyclic guanyl monophosphate, PKG: protein kinase G, N-ECV: neutrophil extracellular vesicles, HNP: human neutrophil peptides, HBP: heparin binding protein, NET: neutrophil extraceullar trap, HMGB1: High mobility group box 1, TLR: toll-like receptor, ADP: adenosine diphosphate, ATP: adenosine triphosphate, TX: thromboxane, IL-R: interleukin receptor, MKC: megakaryocyte, TNFR: tumor necrosis factor receptor, PS: P Selectin, PSGL-1: P Selectin glycoprotein ligand-1, NEUT: neutrophil, PLT: platelet.</p> "> Figure 2
<p>SARS-CoV-2 infection and platelet activation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters endothelial cells through the angiotensin converting enzyme 2 (ACE2) receptor or platelets through CD147, toll-like receptors (TLR), C-type lectin-like receptor 2 (CLEC-2), or via emperipolesis. Several mechanisms are involved in the consequent platelet activation, which leads to the release of platelet granule content, the overexpression of tissue factor (TF), the formation of platelet-leukocyte aggregates, and neutrophil extracellular traps (NETs). Ultimately, the rising severity of the disease could lead to death with significant findings of thrombosis being evidenced in postmortem lung, brain, and heart studies. NO: nitric oxide, vWF: von Willebrand factor, eGC: endothelial glycocalyx, MK: megakaryocytes.</p> ">
Abstract
:1. Introduction
2. Inflammation and Platelet Activation
2.1. Endothelial Dysfunction and Platelet Activation
2.2. Platelet–Neutrophil Interactions in Atherosclerosis
2.3. The Role of Myeloperoxidase and Platelet Toll-Like Receptors
2.4. Cytokines in Platelet Activation
2.5. NLRP3 Inflammasome
2.6. Platelet Factor-4
3. Inflammation and Platelet Activation in Coronavirus Disease-19
4. Therapeutic Implications
5. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study | Agent | Population | Findings |
---|---|---|---|
Di Sabatino et al. [165] | Infliximab | IBD | ↓ TX biosynthesis ↓ sCD40L |
Manfredi et al. [86] | Anti-TNF-α | RA | ↓ platelet-leukocyte and platelet-monocyte aggregates ↓ P-selectin |
Menchen et al. [166] | Infliximab | CD | ↓ sCD40L Non-significant reduction of the enhanced binding of FITC–fibrinogen |
Padfield et al. [157] | Etanercept | AMI | Non-significant effects on platelet activation parameters |
Nielsen et al. [158] | Adalimumab | In vitro | ↑ TRAP-induced platelet aggregation ≥20% |
Tocilizumab | ↓ ADP- and collagen-induced platelet aggregation ≥20% | ||
Canzano et al. [128] | Tocilizumab | COVID-19 (in vitro) | ↓ P-Selectin ↓ Platelet-granulocyte and platelet-neutrophil aggregates |
Shah et al. [159] | Colchicine | Healthy | ↓ P-Selectin and PAC-1 ↓ Platelet-granulocyte and platelet-neutrophil aggregates No effect on homotypic platelet aggregation |
Cirillo et al. [162] | Colchicine | CAD | ↓ TRAP-induced platelet aggregation |
Cimmino [163] | Colchicine | CAD (in vitro) | ADP/Collagen/TRAP-induced platelet aggregation due to cytoskeleton reorganization |
Pennings [164] | Colchicine | Healthy (in vitro) | ↓ P-Selectin ↓ collagen-induced platelet aggregation |
DeSena et al. [167] | Canakinumab | Case of epilepsy | Downregulation of genes associated with platelet activation |
Study | Agent | Target | Findings |
---|---|---|---|
Li et al. [168] | DNAse | NETs | ↓ platelet activation ↓ thrombus formation |
Carminita et al. [169] | DNAse | NETs | ↓ ATP and ADP-induced thrombus formation |
Novotny et al. [173] | Chloramidine | NETs | ↓ arterial thrombus formation |
Clark et al. [174] | Eritoran | TLR4 | ↓ platelet-leukocyte aggregation ↓ platelet-mediated neutrophil degranulation |
Sun et al. [175] | Resveratrol | TLR4 | ↓ TRAP- and collagen-induced platelet aggregation ↓ platelet adhesion and secretion ↓CD40L and platelet factor-4 |
Kovacevic et al. [177] | BT200 | vWF | Inhibition of high shear rate- and ristocetin-induced platelet aggregation |
Nimjee et al. [178] | DTRI-031 | vWF | Inhibition of platelet aggregation and thrombosis |
Dobie et al. [180] | Ibrutinib | BTK | ADAM17-mediated shedding of GPIbα and GPIX in vitro and of GPIbα in vivo |
Ninomoto et al. [181] | Ibrutinib | BTK | ↓ collagen-induced platelet aggregation |
Nicolson et al. [179] | Ibrutinib | BTK | ↓ rhodocytin-induced platelet aggregation and granule secretion |
Acalabrutinib | ↓ rhodocytin- and podoplanin-induced platelet aggregation Blocks CLEC-2-mediated platelet activation and granule secretion | ||
Cornelius et al. [182] | MCC950 | NLRP3 inflammasome | ↓ platelet activation |
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Theofilis, P.; Sagris, M.; Antonopoulos, A.S.; Oikonomou, E.; Tsioufis, C.; Tousoulis, D. Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19. Int. J. Mol. Sci. 2021, 22, 11170. https://doi.org/10.3390/ijms222011170
Theofilis P, Sagris M, Antonopoulos AS, Oikonomou E, Tsioufis C, Tousoulis D. Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19. International Journal of Molecular Sciences. 2021; 22(20):11170. https://doi.org/10.3390/ijms222011170
Chicago/Turabian StyleTheofilis, Panagiotis, Marios Sagris, Alexios S. Antonopoulos, Evangelos Oikonomou, Costas Tsioufis, and Dimitris Tousoulis. 2021. "Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19" International Journal of Molecular Sciences 22, no. 20: 11170. https://doi.org/10.3390/ijms222011170