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Special Issue "Molecular Research on Platelet Activity in Health and Disease 3.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 12852

Special Issue Editors

Dr. Isabella Savini
E-Mail Website
Guest Editor
Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy
Interests: nutrition; platelets; redox state; phenolic compounds; cardiovascular diseases; obesity; metabolic syndrome
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Maria Valeria Catani
E-Mail Website
Guest Editor
Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy
Interests: platelets; oxidative stress; cancer; vitamin C; blood coagulation; inflammation; apoptosis; bioactive lipids; redox-sensitive transcription factors; microRNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Platelets are small anucleated cytoplasmic fragments derived from large megakaryocytes residing in bone marrow that are primarily recognized for their fundamental role in haemostasis and thrombosis. In response to vascular injury, platelets quickly adhere to sub-endothelial matrix proteins, through specific adhesion-signalling receptors whose activation leads to a cascade of events resulting in platelet spreading, granule secretion, aggregation and clot retraction.

To date, a large body of evidence has highlighted the ability of platelets to act as multifunctional cells, which actively influence a widespread range of apparently unrelated patho–physiological events. Platelets, indeed, play a central role in inflammation, an underlying cause in several pathologies (among them cardiovascular disease, obesity, metabolic syndrome and gastrointestinal diseases) as well as in infection, cancer, neurodegeneration and other brain dysfunctions.

For readers, this Special Issue, “Molecular Research on Platelet Activity in Health and Disease”, will provide an up-to-date description of the more intriguing aspects of platelet biology, highly relevant to human diseases.

Dr. Valeria Gasperi
Dr. Isabella Savini
Dr. Maria Valeria Catani
Guest Editors

Manuscript Submission Information

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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

  • platelets
  • hemostasis
  • cancer
  • microRNA
  • inflammatory diseases
  • cell-to-cell crosstalk
  • endothelium
  • infection
  • brain disease

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Published Papers (12 papers)

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Editorial

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Editorial
Molecular Research on Platelet Activity in Health and Disease 3.0
Int. J. Mol. Sci. 2022, 23(10), 5530; https://doi.org/10.3390/ijms23105530 - 16 May 2022
Viewed by 301
Abstract
Zhao and Devine [...] Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)

Research

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Article
Platelet-Rich Fibrin Decreases the Inflammatory Response of Mesenchymal Cells
Int. J. Mol. Sci. 2021, 22(21), 11333; https://doi.org/10.3390/ijms222111333 - 20 Oct 2021
Cited by 6 | Viewed by 1152
Abstract
Chronic inflammation is a pathological process where cells of the mesenchymal lineage become a major source of inflammatory mediators. Platelet-rich fibrin (PRF) has been shown to possess potent anti-inflammatory activity in macrophages, but its impact on mesenchymal cells has not been investigated. The [...] Read more.
Chronic inflammation is a pathological process where cells of the mesenchymal lineage become a major source of inflammatory mediators. Platelet-rich fibrin (PRF) has been shown to possess potent anti-inflammatory activity in macrophages, but its impact on mesenchymal cells has not been investigated. The aim of this study was, therefore, to expose mesenchymal cells to inflammatory cytokines together with lysates generated from liquid platelet-poor plasma (PPP), the cell-rich buffy coat layer (BC; concentrated-PRF or C-PRF), and the remaining red clot layer (RC), following centrifugation of blood. Heating PPP generates an albumin gel (Alb-gel) that when mixed back with C-PRF produces Alb-PRF. Membranes prepared from solid PRF were also subjected to lysis. We report here that lysates of PPP, BC, and PRF decreased the cytokine-induced expression of interleukin 6 (IL6) and nitric oxide synthase (iNOS) in the bone marrow-derived ST2 cells. Consistently, PPP, BC, and PRF greatly decreased the phosphorylation and nuclear translocation of p65 in ST2 cells. The inflammatory response caused by Pam3CSK4 was reduced accordingly. Moreover, PPP, BC, and PRF reduced the enhanced expression of inflammatory mediators IL6 and iNOS in 3T3-L1 pre-adipocyte mesenchymal cells, and iNOS and CCL5 in murine calvarial cells. Surprisingly, PRF lysates were not effective in reducing the inflammatory response of human gingival fibroblasts and HSC2 epithelial cells. The data from the present study suggest that both liquid PRF and solid PRF exert potent anti-inflammatory activity in murine mesenchymal cells. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Article
Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β  Signal Axis through a Cyclic Nucleotides/VASP—Independent Mechanism
Int. J. Mol. Sci. 2021, 22(20), 11109; https://doi.org/10.3390/ijms222011109 - 15 Oct 2021
Cited by 6 | Viewed by 1009
Abstract
The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial [...] Read more.
The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1–5 μM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3β pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Article
Fluorometric Quantification of Human Platelet Polyphosphate Using 4′,6-Diamidine-2-phenylindole Dihydrochloride: Applications in the Japanese Population
Int. J. Mol. Sci. 2021, 22(14), 7257; https://doi.org/10.3390/ijms22147257 - 06 Jul 2021
Cited by 5 | Viewed by 1015
Abstract
Polyphosphate (polyP), a biopolymer of inorganic phosphate, is widely distributed in living organisms. In platelets, polyP is released upon activation and plays important roles in coagulation and tissue regeneration. However, the lack of a specific quantification method has delayed the in-depth study of [...] Read more.
Polyphosphate (polyP), a biopolymer of inorganic phosphate, is widely distributed in living organisms. In platelets, polyP is released upon activation and plays important roles in coagulation and tissue regeneration. However, the lack of a specific quantification method has delayed the in-depth study of polyP. The fluorescent dye 4′,6-diamidine-2-phenylindole dihydrochloride (DAPI) has recently received attention as a promising probe for the visualization and quantification of cellular polyP levels. In this study, we further optimized quantification conditions and applied this protocol in quantification of platelet polyP levels in a Japanese population. Blood samples were collected from non-smoking, healthy Japanese subjects (23 males, 23 females). Washed platelets were fixed and probed with DAPI for fluorometric determination. PolyP levels per platelet count were significantly higher in women than that in men. A moderate negative correlation between age and polyP levels was found in women. Responsiveness to CaCl2 stimulation was also significantly higher in women than that in men. Overall, our optimized protocol requires neither purification nor degradation steps, reducing both the time and bias for reproducible quantification. Thus, we suggest that despite its low specificity, this DAPI-based protocol would be useful in routine laboratory testing to quantify platelet polyP levels efficiently and economically. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Article
The Molecular Aspects of Disturbed Platelet Activation through ADP/P2Y12 Pathway in Multiple Sclerosis
Int. J. Mol. Sci. 2021, 22(12), 6572; https://doi.org/10.3390/ijms22126572 - 18 Jun 2021
Cited by 3 | Viewed by 1050
Abstract
Epidemiological studies confirm a high risk of ischemic events in secondary-progressive multiple sclerosis (SP MS) patients, directly associated with an increased level of pro-thrombotic activity of platelets. Our work aimed to verify potential molecular abnormalities of the platelet P2Y12 receptor expression and [...] Read more.
Epidemiological studies confirm a high risk of ischemic events in secondary-progressive multiple sclerosis (SP MS) patients, directly associated with an increased level of pro-thrombotic activity of platelets. Our work aimed to verify potential molecular abnormalities of the platelet P2Y12 receptor expression and functionality as a cause of an increased risk of thromboembolism observed in the course of MS. We have demonstrated an enhanced platelet reactivity in response to adenosine diphosphate (ADP) in SP MS relative to controls. We have also shown an increased mRNA expression for the P2RY12 gene in both platelets and megakaryocytes, as well as enhanced density of these receptors on the platelet surface. We postulate that one of the reasons for the elevated risk of ischemic events observed in MS may be a genetically or phenotypically reinforced expression of the platelet P2Y12 receptor. In order to analyze the effect of the PAR1 (protease activated receptor type 1) signaling pathway on the expression level of P2Y12, we also analyzed the correlation parameters between P2Y12 expression and the markers of platelet activation in MS induced by selective PAR1 agonist (thrombin receptor activating peptide-6, TRAP-6). Identifying the molecular base responsible for the enlarged pro-thrombotic activity of platelets in SP MS could contribute to the implementation of prevention and targeted treatment, reducing the development of cardiovascular disorders in the course of the disease. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Article
Cellular Response to Individual Components of the Platelet Concentrate
Int. J. Mol. Sci. 2021, 22(9), 4539; https://doi.org/10.3390/ijms22094539 - 26 Apr 2021
Cited by 2 | Viewed by 1015
Abstract
Platelet concentrates and especially their further product platelet lysate, are widely used as a replacement for cell culturing. Platelets contain a broad spectrum of growth factors and bioactive molecules that affect cellular fate. However, the cellular response to individual components of the human [...] Read more.
Platelet concentrates and especially their further product platelet lysate, are widely used as a replacement for cell culturing. Platelets contain a broad spectrum of growth factors and bioactive molecules that affect cellular fate. However, the cellular response to individual components of the human platelet concentrate is still unclear. The aim of this study was to observe cellular behavior according to the individual components of platelet concentrates. The bioactive molecule content was determined. The cells were supplemented with a medium containing 8% (v/v) of platelet proteins in plasma, pure platelet proteins in deionized water, and pure plasma. The results showed a higher concentration of fibrinogen, albumin, insulin growth factor I (IGF-1), keratinocyte growth factor (KGF), and hepatocyte growth factor (HGF), in the groups containing plasma. On the other hand, chemokine RANTES and platelet-derived growth factor bb (PDGF-bb), were higher in the groups containing platelet proteins. The groups containing both plasma and plasma proteins showed the most pronounced proliferation and viability of mesenchymal stem cells and fibroblasts. The platelet proteins alone were not sufficient to provide optimal cell growth and viability. A synergic effect of platelet proteins and plasma was observed. The data indicated the importance of plasma in platelet lysate for cell growth. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Article
The Antithrombotic Agent Pterostilbene Interferes with Integrin αIIbβ3-Mediated Inside-Out and Outside-In Signals in Human Platelets
Int. J. Mol. Sci. 2021, 22(7), 3643; https://doi.org/10.3390/ijms22073643 - 31 Mar 2021
Cited by 5 | Viewed by 1049
Abstract
Platelets play a crucial role in the physiology of primary hemostasis and pathological processes such as arterial thrombosis; thus, developing a therapeutic target that prevents platelet activation can reduce arterial thrombosis. Pterostilbene (PTE) has remarkable pharmacological activities, including anticancer and neuroprotection. Few studies [...] Read more.
Platelets play a crucial role in the physiology of primary hemostasis and pathological processes such as arterial thrombosis; thus, developing a therapeutic target that prevents platelet activation can reduce arterial thrombosis. Pterostilbene (PTE) has remarkable pharmacological activities, including anticancer and neuroprotection. Few studies have reported the effects of pterostilbene on platelet activation. Thus, we examined the inhibitory mechanisms of pterostilbene in human platelets and its role in vascular thrombosis prevention in mice. At low concentrations (2–8 μM), pterostilbene strongly inhibited collagen-induced platelet aggregation. Furthermore, pterostilbene markedly diminished Lyn, Fyn, and Syk phosphorylation and hydroxyl radical formation stimulated by collagen. Moreover, PTE directly hindered integrin αIIbβ3 activation through interfering with PAC-1 binding stimulated by collagen. In addition, pterostilbene affected integrin αIIbβ3-mediated outside-in signaling, such as integrin β3, Src, and FAK phosphorylation, and reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Furthermore, pterostilbene substantially prolonged the occlusion time of thrombotic platelet plug formation in mice. This study demonstrated that pterostilbene exhibits a strong activity against platelet activation through the inhibition of integrin αIIbβ3-mediated inside-out and outside-in signaling, suggesting that pterostilbene can serve as a therapeutic agent for thromboembolic disorders. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Article
Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes
Int. J. Mol. Sci. 2021, 22(7), 3292; https://doi.org/10.3390/ijms22073292 - 24 Mar 2021
Cited by 1 | Viewed by 1011
Abstract
In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to [...] Read more.
In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to upregulation of ORAI1 and STIM1 includes transcription factor NFAT5 and serum and glucocorticoid-inducible kinase SGK1. In vascular smooth muscle cells, the effect of hyperphosphatemia on ORAI1/STIM1 expression and SOCE is suppressed by Mg2+ and the calcium-sensing receptor (CaSR) agonist Gd3+. The present study explored whether sustained exposure to Mg2+ or Gd3+ interferes with the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. To this end, human megakaryocytic Meg-01 cells were treated with 2 mM ß-glycerophosphate for 24 h in the absence and presence of either 1.5 mM MgCl2 or 50 µM GdCl3. Transcript levels were estimated utilizing q-RT-PCR, protein abundance by Western blotting, cytosolic Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and SOCE from the increase in [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, Mg2+ and Gd3+ upregulated CaSR and blunted or virtually abolished the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. In conclusion, Mg2+ and the CaSR agonist Gd3+ interfere with phosphate-induced dysregulation of [Ca2+]i in megakaryocytes. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Communication
In Ovarian Cancer Multicellular Spheroids, Platelet Releasate Promotes Growth, Expansion of ALDH+ and CD133+ Cancer Stem Cells, and Protection against the Cytotoxic Effects of Cisplatin, Carboplatin and Paclitaxel
Int. J. Mol. Sci. 2021, 22(6), 3019; https://doi.org/10.3390/ijms22063019 - 16 Mar 2021
Cited by 12 | Viewed by 1219
Abstract
A high platelet count is associated with a poor prognosis in ovarian cancer (OvCa). Despite good clinical responses with platinating agents in combination with taxanes, numerous OvCa patients relapse due to chemotherapy resistance. Here, we report that treatment of OvCa cells A2780, OVCAR5 [...] Read more.
A high platelet count is associated with a poor prognosis in ovarian cancer (OvCa). Despite good clinical responses with platinating agents in combination with taxanes, numerous OvCa patients relapse due to chemotherapy resistance. Here, we report that treatment of OvCa cells A2780, OVCAR5 and MDAH with releasate from activated platelets (PR) promoted multicellular tumor spheroid (MCTS) formation. These OvCa-MCTSs had increased percentages of CD133+ and aldehyde dehydrogenase (ALDH)+ cells, bona fide markers of OvCa cancer stem cells (CSCs). PR increased OVCAR5- and MDAH-MCTS viability and decreased the cytotoxic and pro-apoptotic effects of paclitaxel, cisplatin and carboplatin. PR increased the volume of spontaneously formed OVCAR8-MCTSs and counteracted their size reduction due to cisplatin, carboplatin and paclitaxel treatment. PR promoted the survival of ALDH+ and CD133+ OvCa cells during cisplatin, carboplatin and paclitaxel treatment. In conclusion, molecules and growth factors released by activated platelets (EGF, PDGF, TGF-β, IGF and CCL5) may protect tumor cells from chemotherapy by promoting the expansion of ALDH+ and CD133+ OvCa-CSCs, favoring drug resistance and tumor relapse. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Review

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Review
Platelet-Released Factors: Their Role in Viral Disease and Applications for Extracellular Vesicle (EV) Therapy
Int. J. Mol. Sci. 2022, 23(4), 2321; https://doi.org/10.3390/ijms23042321 - 19 Feb 2022
Cited by 1 | Viewed by 788
Abstract
Platelets, which are small anuclear cell fragments, play important roles in thrombosis and hemostasis, but also actively release factors that can both suppress and induce viral infections. Platelet-released factors include sCD40L, microvesicles (MVs), and alpha granules that have the capacity to exert either [...] Read more.
Platelets, which are small anuclear cell fragments, play important roles in thrombosis and hemostasis, but also actively release factors that can both suppress and induce viral infections. Platelet-released factors include sCD40L, microvesicles (MVs), and alpha granules that have the capacity to exert either pro-inflammatory or anti-inflammatory effects depending on the virus. These factors are prime targets for use in extracellular vesicle (EV)-based therapy due to their ability to reduce viral infections and exert anti-inflammatory effects. While there are some studies regarding platelet microvesicle-based (PMV-based) therapy, there is still much to learn about PMVs before such therapy can be used. This review provides the background necessary to understand the roles of platelet-released factors, how these factors might be useful in PMV-based therapy, and a critical discussion of current knowledge of platelets and their role in viral diseases. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Review
The Missing Pieces to the Cold-Stored Platelet Puzzle
Int. J. Mol. Sci. 2022, 23(3), 1100; https://doi.org/10.3390/ijms23031100 - 20 Jan 2022
Cited by 2 | Viewed by 601
Abstract
Cold-stored platelets are making a comeback. They were abandoned in the late 1960s in favor of room-temperature stored platelets due to the need for longer post-transfusion platelet recoverability and survivability in patients with chronic thrombocytopenia. However, the current needs for platelet transfusions are [...] Read more.
Cold-stored platelets are making a comeback. They were abandoned in the late 1960s in favor of room-temperature stored platelets due to the need for longer post-transfusion platelet recoverability and survivability in patients with chronic thrombocytopenia. However, the current needs for platelet transfusions are rapidly changing. Today, more platelets are given to patients who are actively bleeding, such as ones receiving cardiac surgeries. It has been established that cold-stored platelets are more hemostatically effective, have reduced bacterial growth, and have longer potential shelf lives. These compelling characteristics led to the recent interest in bringing back cold-stored platelets to the blood systems. However, before reinstating cold-stored platelets in the clinics again, a thorough investigation of in vitro storage characteristics and in vivo transfusion effects is required. This review aims to provide an update on the recent research efforts into the storage characteristics and functions of cold-stored platelets using modern investigative tools. We will also discuss efforts made to improve cold-stored platelets to be a better and safer product. Finally, we will finish off with discussing the relevance of in vitro data to in vivo transfusion results and provide insights and directions for future investigations of cold-stored platelets. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Review
Proteomics: A Tool to Study Platelet Function
Int. J. Mol. Sci. 2021, 22(9), 4776; https://doi.org/10.3390/ijms22094776 - 30 Apr 2021
Cited by 4 | Viewed by 1761
Abstract
Platelets are components of the blood that are highly reactive, and they quickly respond to multiple physiological and pathophysiological processes. In the last decade, it became clear that platelets are the key components of circulation, linking hemostasis, innate, and acquired immunity. Protein composition, [...] Read more.
Platelets are components of the blood that are highly reactive, and they quickly respond to multiple physiological and pathophysiological processes. In the last decade, it became clear that platelets are the key components of circulation, linking hemostasis, innate, and acquired immunity. Protein composition, localization, and activity are crucial for platelet function and regulation. The current state of mass spectrometry-based proteomics has tremendous potential to identify and quantify thousands of proteins from a minimal amount of material, unravel multiple post-translational modifications, and monitor platelet activity during drug treatments. This review focuses on the role of proteomics in understanding the molecular basics of the classical and newly emerging functions of platelets. including the recently described role of platelets in immunology and the development of COVID-19.The state-of-the-art proteomic technologies and their application in studying platelet biogenesis, signaling, and storage are described, and the potential of newly appeared trapped ion mobility spectrometry (TIMS) is highlighted. Additionally, implementing proteomic methods in platelet transfusion medicine, and as a diagnostic and prognostic tool, is discussed. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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