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Advances in Biological Functions of Platelet

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (29 May 2020) | Viewed by 35298

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Dr. Isabella Russo

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Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole, 10, Orbassano, I-10043 Turin, Italy
Interests: platelets function; nitric oxide; haemostasis; thrombosis; anti-platelet drugs; platelet dysfunction in metabolic diseases
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Dear Colleagues,

Platelets, best known as primary mediators of hemostasis and thrombosis, are a critical component of blood vessel walls. As secretory cells, platelets can release multiple substances from storage granules, biomediators and membrane vesicles, influencing both physiological and pathophysiological processes. Conversely, platelets can uptake plasma and cellular components, influencing platelet responsiveness. The analysis of platelet function through the development of powerful imaging techniques, as well as the identification of cells and new molecules that regulate their activation and aggregation within vessels, are instrumental to better understand the mechanisms through which platelets protect or damage organisms. These analyses provide useful information for studying the pathogenesis of many disease states.

This Special Issue of the International Journal of Molecular Sciences, entitled “Advances in Biological Functions of Platelets”, will focus on recent advances in platelet function research, such as platelet action or the release of substances or micro-particles containing platelet miRNA, enzymes, proteins, and small molecules with roles in healthy conditions and as drivers of immunity, inflammation, angiogenesis, and tumor growth. Contributions on these and related topics are welcome, including original research and reviews. We particularly welcome submissions from postdocs, PhD students, and young researchers.

Dr. Isabella Russo
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

platelet microparticles
thrombosis
inflammation
oxidative stress
antiplatelet drug
signal transduction
immunity
tumor growth

Published Papers (9 papers)

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Research

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16 pages, 2384 KiB

Open AccessArticle

The Serine/Threonine Protein Phosphatase 2A (PP2A) Regulates Syk Activity in Human Platelets

by Stephanie Makhoul, Elena Kumm, Pengyu Zhang, Ulrich Walter and Kerstin Jurk

Int. J. Mol. Sci. 2020, 21(23), 8939; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238939 - 25 Nov 2020

Cited by 6 | Viewed by 2787

Abstract

Distinct membrane receptors activate platelets by Src-family-kinase (SFK)-, immunoreceptor-tyrosine-based-activation-motif (ITAM)-dependent stimulation of spleen tyrosine kinase (Syk). Recently, we reported that platelet activation via glycoprotein (GP) VI or GPIbα stimulated the well-established Syk tyrosine (Y)-phosphorylation, but also stoichiometric, transient protein kinase C (PKC)-mediated Syk serine(S)297 phosphorylation in the regulatory interdomain-B, suggesting possible feedback inhibition. The transient nature of Syk S297 phosphorylation indicated the presence of an unknown Syk pS297 protein phosphatase. In this study, we hypothesize that the S-protein phosphatase 2A (PP2A) is responsible for Syk pS297 dephosphorylation, thereby affecting Syk Y-phosphorylation and activity in human washed platelets. Using immunoblotting, we show that specific inhibition of PP2A by okadaic acid (OA) alone leads to stoichiometric Syk S297 phosphorylation, as analyzed by Zn²⁺-Phos-tag gels, without affecting Syk Y-phosphorylation. Pharmacological inhibition of Syk by PRT060318 or PKC by GF109203X only minimally reduced OA-induced Syk S297 phosphorylation. PP2A inhibition by OA preceding GPVI-mediated platelet activation induced by convulxin extended Syk S297 phosphorylation but inhibited Syk Y-phosphorylation. Our data demonstrate a novel biochemical and functional link between the S-protein phosphatase PP2A and the Y-protein kinase Syk in human platelets, and suggest that PP2A represents a potential enhancer of GPVI-mediated Syk activity caused by Syk pS297 dephosphorylation. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Platelet)

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16 pages, 2841 KiB

Open AccessArticle

Platelet-Reactive Antibodies in Patients after Ischaemic Stroke—An Epiphenomenon or a Natural Protective Mechanism

by Young Eun Park, Rushi Penumarthy, Paul P. Sun, Caroline Y. Kang, Marie-Christine Morel-Kopp, Jonathan Downing, Taryn N. Green, Tracey Immanuel, Christopher M. Ward, Deborah Young, Matthew J. During, P. Alan Barber and Maggie L. Kalev-Zylinska

Int. J. Mol. Sci. 2020, 21(21), 8398; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218398 - 09 Nov 2020

Cited by 1 | Viewed by 2352

Abstract

Ischaemic brain damage induces autoimmune responses, including the production of autoantibodies with potential neuroprotective effects. Platelets share unexplained similarities with neurons, and the formation of anti-platelet antibodies has been documented in neurological disorders. The aim of this study was to investigate the presence of anti-platelet antibodies in the peripheral blood of patients after ischaemic stroke and determine any clinical correlations. Using a flow cytometry-based platelet immunofluorescence method, we detected platelet-reactive antibodies in 15 of 48 (31%) stroke patients and two of 50 (4%) controls (p < 0.001). Western blotting revealed heterogeneous reactivities with platelet proteins, some of which overlapped with brain proteins. Stroke patients who carried anti-platelet antibodies presented with larger infarcts and more severe neurological dysfunction, which manifested as higher scores on the National Institutes of Health Stroke Scale (NIHSS; p = 0.009), but they had a greater recovery in the NIHSS by the time of hospital discharge (day 7 ± 2) compared with antibody-negative patients (p = 0.043). Antibodies from stroke sera reacted more strongly with activated platelets (p = 0.031) and inhibited platelet aggregation by up to 30.1 ± 2.8% (p < 0.001), suggesting the potential to interfere with thrombus formation. In conclusion, platelet-reactive antibodies can be found in patients soon after ischaemic stroke and correlate with better short-term outcomes, suggesting a potential novel mechanism limiting thrombosis. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Platelet)

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18 pages, 1270 KiB

Open AccessArticle

Association between High On-Aspirin Platelet Reactivity and Reduced Superoxide Dismutase Activity in Patients Affected by Type 2 Diabetes Mellitus or Primary Hypercholesterolemia

by Cristina Barale, Franco Cavalot, Chiara Frascaroli, Katia Bonomo, Alessandro Morotti, Angelo Guerrasio and Isabella Russo

Int. J. Mol. Sci. 2020, 21(14), 4983; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144983 - 15 Jul 2020

Cited by 11 | Viewed by 2188

Abstract

Platelet hyperactivation is involved in the established prothrombotic condition of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM) and familial hypercholesterolemia (HC), justifying the therapy with aspirin, a suppressor of thromboxane synthesis through the irreversible inhibition of cyclooxygenase-1 (COX-1), to prevent cardiovascular diseases. However, some patients on aspirin show a higher than expected platelet reactivity due, at least in part, to a pro-oxidant milieu. The aim of this study was to investigate platelet reactivity in T2DM (n = 103) or HC (n = 61) patients (aspirin, 100 mg/day) and its correlation with biomarkers of redox function including the superoxide anion scavenger superoxide dismutase (SOD) and the in vivo marker of oxidative stress urinary 8-iso-prostaglandin F_2α. As results, in T2DM and HC subjects the prevalence of high on-aspirin platelet reactivity was comparable when both non-COX-1-dependent and COX-1-dependent assays were performed, and platelet reactivity is associated with a lower SOD activity that in a stepwise linear regression appears as the only predictor of platelet reactivity. To conclude, in T2DM and HC, similarly, the impairment of redox equilibrium associated with a decrease of SOD activity could contribute to a suboptimal response to aspirin. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Platelet)

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17 pages, 2380 KiB

Open AccessArticle

Platelet-Released Growth Factors and Platelet-Rich Fibrin Induce Expression of Factors Involved in Extracellular Matrix Organization in Human Keratinocytes

by Andreas Bayer, Bernard Wijaya, Lena Möbus, Franziska Rademacher, Meno Rodewald, Mersedeh Tohidnezhad, Thomas Pufe, Daniel Drücke, Regine Gläser and Jürgen Harder

Int. J. Mol. Sci. 2020, 21(12), 4404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124404 - 20 Jun 2020

Cited by 13 | Viewed by 2954

Abstract

Platelet-released growth factor (PRGF) is a thrombocyte concentrate lysate which, like its clinically equivalent variations (e.g., Vivostat PRF^® (platelet-rich fibrin)), is known to support the healing of chronic and hard-to-heal wounds. However, studies on the effect of PRGF on keratinocytes remain scarce. This study aims to identify genes in keratinocytes that are significantly influenced by PRGF. Therefore, we performed a whole transcriptome and gene ontology (GO) enrichment analysis of PRGF-stimulated human primary keratinocytes. This revealed an increased expression of genes involved in extracellular matrix (ECM) organization. Real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) analysis confirmed the PRGF-mediated induction of selected ECM-related factors such as transforming growth factor beta-induced protein, fibronectin 1, matrix metalloproteinase-9, transglutaminase 2, fermitin family member 1, collagen type I alpha 1 and collagen type XXII alpha 1. PRGF-induced expression of the above factors was influenced by blockade of the epidermal growth factor receptor (EGFR), a receptor playing a crucial role in wound healing. A differential induction of the investigated factors was also detected in skin explants exposed to PRGF and in experimentally generated in vivo wounds treated with Vivostat PRF^®. Together, our study indicates that the induction of ECM-related factors may contribute to the beneficial wound-healing effects of PRGF-based formulations. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Platelet)

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15 pages, 2277 KiB

Open AccessArticle

Platelet Activation Is Triggered by Factors Secreted by Senescent Endothelial HMEC-1 Cells In Vitro

by Whitney Venturini, Alexandra Olate-Briones, Claudio Valenzuela, Diego Méndez, Eduardo Fuentes, Angel Cayo, Daniel Mancilla, Raul Segovia, Nelson E. Brown and Rodrigo Moore-Carrasco

Int. J. Mol. Sci. 2020, 21(9), 3287; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093287 - 06 May 2020

Cited by 16 | Viewed by 4165

Abstract

Aging is one of the main risk factors for the development of chronic diseases, with both the vascular endothelium and platelets becoming functionally altered. Cellular senescence is a form of permanent cell cycle arrest initially described in primary cells propagated in vitro, although it can also be induced by anticancer drugs and other stressful stimuli. Attesting for the complexity of the senescent phenotype, senescent cells synthesize and secrete a wide variety of bioactive molecules. This “senescence-associated secretory phenotype” (SASP) endows senescent cells with the ability to modify the tissue microenvironment in ways that may be relevant to the development of various physiological and pathological processes. So far, however, the direct role of factors secreted by senescent endothelial cells on platelet function remains unknown. In the present work, we explore the effects of SASP factors derived from senescent endothelial cells on platelet function. To this end, we took advantage of a model in which immortalized endothelial cells (HMEC-1) were induced to senesce following exposure to doxorubicin, a chemotherapeutic drug widely used in the clinic. Our results indicate that (1) low concentrations of doxorubicin induce senescence in HMEC-1 cells; (2) senescent HMEC-1 cells upregulate the expression of selected components of the SASP and (3) the media conditioned by senescent endothelial cells are capable of inducing platelet activation and aggregation. These results suggest that factors secreted by senescent endothelial cells in vivo could have a relevant role in the platelet activation observed in the elderly or in patients undergoing therapeutic stress. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Platelet)

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11 pages, 2917 KiB

Open AccessArticle

Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways

by Elmira R. Mordakhanova, Tatiana A. Nevzorova, Gulnaz E. Synbulatova, Lubica Rauova, John W. Weisel and Rustem I. Litvinov

Int. J. Mol. Sci. 2020, 21(7), 2556; https://doi.org/10.3390/ijms21072556 - 07 Apr 2020

Cited by 8 | Viewed by 2999

Abstract

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis. HIT is caused by antibodies that recognize complexes of platelet factor 4 and heparin. The pathogenic mechanisms of this condition are not fully understood. In this study, we used flow cytometry, fluorimetry, and Western blot analysis to study the direct effects of pathogenic immune complexes containing platelet factor 4 on human platelets isolated by gel-filtration. HIT-like pathogenic immune complexes initially caused pronounced activation of platelets detected by an increased expression of phosphatidylserine and P-selectin. This activation was mediated either directly through the FcγRIIA receptors or indirectly via protease-activated receptor 1 (PAR1) receptors due to thrombin generated on or near the surface of activated platelets. The immune activation was later followed by the biochemical signs of cell death, such as mitochondrial membrane depolarization, up-regulation of Bax, down-regulation of Bcl-X_L, and moderate activation of procaspase 3 and increased calpain activity. The results show that platelet activation under the action of HIT-like immune complexes is accompanied by their death through complex apoptotic and calpain-dependent non-apoptotic pathways that may underlie the low platelet count in HIT. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Platelet)

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19 pages, 7295 KiB

Open AccessArticle

Systematic Comparison of the Effect of Four Clinical-Grade Platelet Rich Hemoderivatives on Osteoblast Behaviour

by Tulio Fernández-Medina, Cedryck Vaquette and Sašo Ivanovski

Int. J. Mol. Sci. 2019, 20(24), 6243; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246243 - 11 Dec 2019

Cited by 31 | Viewed by 4701

Abstract

Hemoderivatives have utilized in an empirical manner, driven by clinical considerations, leading to the development of a plethora of manufacturing protocols. The purpose of this study was to investigate the composition and bioactivity of four common clinical-grade hemoderivates prepared using standardised methods. Four different hemoderivatives were obtained from sheep blood and divided into two groups: A-PRF/i-PRF (fresh) and P-PRP/L-PRP (anticoagulated). Thrombus (CLOT) was used as a control. Thrombocyte quantification, growth factor composition (IGF-I, VEGF, PDGF-BB, BMP-2), cell viability, migration and mineralization assay were evaluated. Platelet recovery was superior for L-PRP followed by P-PRP. A significant cumulative release of IGF-I and PDGF-BB was noted for A-PRF and L-PRP groups at early time points. Similar release profiles of BMP-2 and VEGF were noted in all protocols. Cell viability and migration assay have demonstrated a detrimental effect when the concentration was ≥60%. Moreover, at Day 21, i-PRF have demonstrated superior mineralisation properties when compared to all groups. A negative impact of A-PRF was demonstrated at high concentrations. Despite its low content in growth factors, i-PRF was the best performing blood product for inducing osteoblast mineralisation, and therefore could be the candidate of choice for utilisation in bone tissue engineering applications. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Platelet)

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Review

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31 pages, 999 KiB

Open AccessReview

Beyond Haemostasis and Thrombosis: Platelets in Depression and Its Co-Morbidities

by Benedetta Izzi, Alfonsina Tirozzi, Chiara Cerletti, Maria Benedetta Donati, Giovanni de Gaetano, Marc F. Hoylaerts, Licia Iacoviello and Alessandro Gialluisi

Int. J. Mol. Sci. 2020, 21(22), 8817; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228817 - 21 Nov 2020

Cited by 33 | Viewed by 4748

Abstract

Alongside their function in primary haemostasis and thrombo-inflammation, platelets are increasingly considered a bridge between mental, immunological and coagulation-related disorders. This review focuses on the link between platelets and the pathophysiology of major depressive disorder (MDD) and its most frequent comorbidities. Platelet- and neuron-shared proteins involved in MDD are functionally described. Platelet-related studies performed in the context of MDD, cardiovascular disease, and major neurodegenerative, neuropsychiatric and neurodevelopmental disorders are transversally presented from an epidemiological, genetic and functional point of view. To provide a complete scenario, we report the analysis of original data on the epidemiological link between platelets and depression symptoms suggesting moderating and interactive effects of sex on this association. Epidemiological and genetic studies discussed suggest that blood platelets might also be relevant biomarkers of MDD prediction and occurrence in the context of MDD comorbidities. Finally, this review has the ambition to formulate some directives and perspectives for future research on this topic. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Platelet)

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35 pages, 2098 KiB

Open AccessReview

ROS in Platelet Biology: Functional Aspects and Methodological Insights

by Elena Masselli, Giulia Pozzi, Mauro Vaccarezza, Prisco Mirandola, Daniela Galli, Marco Vitale, Cecilia Carubbi and Giuliana Gobbi

Int. J. Mol. Sci. 2020, 21(14), 4866; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144866 - 09 Jul 2020

Cited by 104 | Viewed by 7614

Abstract

Reactive oxygen species (ROS) and mitochondria play a pivotal role in regulating platelet functions. Platelet activation determines a drastic change in redox balance and in platelet metabolism. Indeed, several signaling pathways have been demonstrated to induce ROS production by NAPDH oxidase (NOX) and mitochondria, upon platelet activation. Platelet-derived ROS, in turn, boost further ROS production and consequent platelet activation, adhesion and recruitment in an auto-amplifying loop. This vicious circle results in a platelet procoagulant phenotype and apoptosis, both accounting for the high thrombotic risk in oxidative stress-related diseases. This review sought to elucidate molecular mechanisms underlying ROS production upon platelet activation and the effects of an altered redox balance on platelet function, focusing on the main advances that have been made in platelet redox biology. Furthermore, given the increasing interest in this field, we also describe the up-to-date methods for detecting platelets, ROS and the platelet bioenergetic profile, which have been proposed as potential disease biomarkers. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Platelet)

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