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The Role of Platelets in Human Health and Disease

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 35527

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Prof. Dr. Ángel García

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Guest Editor

Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Avda. Barcelona s/n, 15782 Santiago de Compostela, Spain
Interests: platelet proteomics; anti-thrombotics; extracellular vesicles; platelet drug targets and biomarkers in obesity and cardiovascular disease

Dr. Alice Pollitt

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Co-Guest Editor

School of Biological Sciences, Health and Life Sciences Building, University of Reading, Whiteknights Reading RG6 6EX, UK
Interests: Cardiovascular biology; platelet-cell communication; microscopy; receptors; signalling; lymphatic development

Special Issue Information

Dear Colleagues,

Platelets play a fundamental role in thrombosis and hemostasis through the activation of multiple receptors and the release of their intracellular granules content. Moreover, platelets are also the main contributors to the extracellular vesicles that circulate in plasma, whose numbers increase in several pathological circumstances. Indeed, in recent years, the role of platelets has expanded beyond thrombosis and hemostasis and is known their involvement in inflammation, cancer metastasis, and infection, among others. Platelet reactivity is altered in various pathological circumstances, such as atherothrombosis, acute coronary syndromes, obesity, or diabetes. The present Special Issue aims to cover a series of original research and review articles focusing on the role of platelets in health and disease. They may include signaling and pharmacological studies, characterization of the platelet membrane components by biochemical approaches, studies of the platelet releasate and -omics studies. Special emphasis will be put on the combination of the above with functional studies that may help to gain insights into platelet function, specially since a pathological point of view. Articles covering the role of platelets in disease will be welcome, including recent studies on COVID-19. We hope that this Special Issue will be of interest to a broad audience and will bring attention to the relevant role platelets play in human health and disease.

Prof. Dr. Ángel García
Guest Editor
Dr. Alice Pollitt
Co-Guest Editor

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Keywords

platelets
thrombosis
platelet-related diseases
platelet biomarkers and drug targets

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Published Papers (10 papers)

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Research

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13 pages, 2334 KiB

Open AccessArticle

Platelet Lipidome Fingerprint: New Assistance to Characterize Platelet Dysfunction in Obesity

by Gaëtan Chicanne, Maria N. Barrachina, Anaelle Durbec, Justine Bertrand-Michel, Sara Troitiño, Lidia Hermida-Nogueira, Aurelio M. Sueiro, María Pardo, Bernard Payrastre and Ángel García

Int. J. Mol. Sci. 2022, 23(15), 8326; https://doi.org/10.3390/ijms23158326 - 28 Jul 2022

Cited by 10 | Viewed by 4073

Abstract

Obesity is associated with a pro-inflammatory and pro-thrombotic state that supports atherosclerosis progression and platelet hyper-reactivity. During the last decade, the platelet lipidome has been considered a treasure trove, as it is a source of biomarkers for preventing and treating different pathologies. The goal of the present study was to determine the lipid profile of platelets from non-diabetic, severely obese patients compared with their age- and sex-matched lean controls. Lipids from washed platelets were isolated and major phospholipids, sphingolipids and neutral lipids were analyzed either by gas chromatography or by liquid chromatography coupled to mass spectrometry. Despite a significant increase in obese patient’s plasma triglycerides, there were no significant differences in the levels of triglycerides in platelets among the two groups. In contrast, total platelet cholesterol was significantly decreased in the obese group. The profiling of phospholipids showed that phosphatidylcholine and phosphatidylethanolamine contents were significantly reduced in platelets from obese patients. On the other hand, no significant differences were found in the sphingomyelin and ceramide levels, although there was also a tendency for reduced levels in the obese group. The outline of the glycerophospholipid and sphingolipid molecular species (fatty-acyl profiles) was similar in the two groups. In summary, these lipidomics data indicate that platelets from obese patients have a unique lipid fingerprint that may guide further studies and provide mechanistic-driven perspectives related to the hyperactivate state of platelets in obesity. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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19 pages, 4560 KiB

Open AccessArticle

Anti-Thrombotic Effects of Artesunate through Regulation of cAMP and PI3K/MAPK Pathway on Human Platelets

by Shin-Sook Yoon, Hyuk-Woo Kwon, Jung-Hae Shin, Man Hee Rhee, Chang-Eun Park and Dong-Ha Lee

Int. J. Mol. Sci. 2022, 23(3), 1586; https://doi.org/10.3390/ijms23031586 - 29 Jan 2022

Cited by 17 | Viewed by 3745

Abstract

Normal activation of platelets and their aggregation are crucial for proper hemostasis. It appears that excessive or abnormal aggregation of platelets may bring about cardiovascular diseases such as stroke, atherosclerosis, and thrombosis. For this reason, finding a substance that can regulate platelet aggregation or suppress aggregation will aid in the prevention and treatment of cardiovascular diseases. Artesunate is a compound extracted from the plant roots of Artemisia or Scopolia, and its effects have shown to be promising in areas of anticancer and Alzheimer’s disease. However, the role and mechanisms by which artesunate affects the aggregation of platelets and the formation of a thrombus are currently not understood. This study examines the ways artesunate affects the aggregation of platelets and the formation of a thrombus on platelets induced by U46619. As a result, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) production were increased significantly by artesunate relative to the doses, as well as phosphorylated vasodilator-stimulated phosphoprotein (VASP) and inositol 1,4,5-trisphosphate receptor (IP₃R), substrates to cAMP-dependent kinase and cGMP-dependent kinase, in a significant manner. The Ca²⁺, normally mobilized from the dense tubular system, was inhibited due to IP₃R phosphorylation from artesunate, and phosphorylated VASP aided in inhibiting platelet activity via αIIb/β₃ platelet membrane inactivation and inhibiting fibrinogen binding. In addition, MAPK and PI3K/Akt phosphorylation was inhibited via artesunate in a significant manner, causing the production of TXA₂ and intracellular granular secretion (serotonin and ATP release) to be reduced. Therefore, we suggest that artesunate has value as a substance that inhibits platelet aggregation and thrombus formation through an antiplatelet mechanism. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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15 pages, 4261 KiB

Open AccessArticle

Differential Effects of Platelet Factor 4 (CXCL4) and Its Non-Allelic Variant (CXCL4L1) on Cultured Human Vascular Smooth Muscle Cells

by Dawid M. Kaczor, Rafael Kramann, Tilman M. Hackeng, Leon J. Schurgers and Rory R. Koenen

Int. J. Mol. Sci. 2022, 23(2), 580; https://doi.org/10.3390/ijms23020580 - 6 Jan 2022

Cited by 9 | Viewed by 3138

Abstract

Platelet factor 4 (CXCL4) is a chemokine abundantly stored in platelets. Upon injury and during atherosclerosis, CXCL4 is transported through the vessel wall where it modulates the function of vascular smooth muscle cells (VSMCs) by affecting proliferation, migration, gene expression and cytokine release. Variant CXCL4L1 is distinct from CXCL4 in function and expression pattern, despite a minor three-amino acid difference. Here, the effects of CXCL4 and CXCL4L1 on the phenotype and function of human VSMCs were compared in vitro. VSMCs were found to constitutively express CXCL4L1 and only exogenously added CXCL4 was internalized by VSMCs. Pre-treatment with heparin completely blocked CXCL4 uptake. A role of the putative CXCL4 receptors CXCR3 and DARC in endocytosis was excluded, but LDL receptor family members appeared to be involved in the uptake of CXCL4. Incubation of VSMCs with both CXCL4 and CXCL4L1 resulted in decreased expression of contractile marker genes and increased mRNA levels of KLF4 and NLRP3 transcription factors, yet only CXCL4 stimulated proliferation and calcification of VSMCs. In conclusion, CXCL4 and CXCL4L1 both modulate gene expression, yet only CXCL4 increases the division rate and formation of calcium-phosphate crystals in VSMCs. CXCL4 and CXCL4L1 may play distinct roles during vascular remodeling in which CXCL4 induces proliferation and calcification while endogenously expressed CXCL4L1 governs cellular homeostasis. The latter notion remains a subject for future investigation. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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13 pages, 2294 KiB

Open AccessCommunication

Practical Considerations of Dissolved Oxygen Levels for Platelet Function under Hypoxia

by Branden Kusanto, Andrew Gordon, Leigh Naylor-Adamson, Lloyd Atkinson, Charlie Coupland, Zoe Booth, Yusra Ahmed, Isabel M. Pires, Graeme J. Stasiuk, Roger Sturmey, Simon D. J. Calaminus and Mònica Arman

Int. J. Mol. Sci. 2021, 22(24), 13223; https://doi.org/10.3390/ijms222413223 - 8 Dec 2021

Cited by 1 | Viewed by 3081

Abstract

Investigating human platelet function in low-oxygen environments is important in multiple settings, including hypobaric hypoxia (e.g., high altitude), sea level hypoxia-related disease, and thrombus stability. These studies often involve drawing blood from which platelets are isolated and analysed at atmospheric conditions or re-exposed to low oxygen levels in hypoxia chambers before testing. However, it remains unknown how the in vitro handling of the samples itself changes their dissolved oxygen concentration, which might affect platelet function and experimental results. Here, we prepared healthy donor platelet-rich plasma and washed platelet (WP) suspensions and exposed them to 2% oxygen. We found that the use of hypoxia pre-equilibrated tubes, higher platelet concentrations (>2 × 10⁸/mL versus 2 × 10⁷/mL), smaller volumes (600 µL versus 3 mL), and presence of plasma reduced the time for samples to reach 2% oxygen. Notably, oxygen levels decreased below 2% in most suspensions, but also in WP maintained at atmospheric 21% oxygen. Additionally, platelet spreading on fibrinogen was decreased when using hypoxic fibrinogen-coated culture plates regardless of the oxygen percentage (2% or 21%) in which platelet incubation took place. Thus, sample handling and experimental conditions should be carefully monitored in platelet-hypoxia studies as they might compromise results interpretation and comparison across studies. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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15 pages, 2271 KiB

Open AccessArticle

Insulin-like Growth Factor Binding Protein-2 (IGFBP2) Is a Key Molecule in the MACC1-Mediated Platelet Communication and Metastasis of Colorectal Cancer Cells

by Reza Haschemi, Dennis Kobelt, Elisabeth Steinwarz, Martin Schlesinger, Ulrike Stein and Gerd Bendas

Int. J. Mol. Sci. 2021, 22(22), 12195; https://doi.org/10.3390/ijms222212195 - 11 Nov 2021

Cited by 11 | Viewed by 2790

Abstract

Tumor cell crosstalk with platelets and, subsequently, their activation are key steps in hematogenous tumor metastasis. MACC1 is an oncogene involved in molecular pathogenesis of colorectal cancer (CRC) and other solid tumor entities, mediating motility and metastasis, making MACC1 an accepted prognostic biomarker. However, the impact of MACC1 on platelet activation has not yet been addressed. Here, we investigated the activation of platelets by human CRC cells upon MACC1 modulation, indicated by platelet aggregation and granule release. These approaches led to the identification of insulin-like growth factor binding protein-2 (IGFBP2) as a functional downstream molecule of MACC1, affecting communication with platelets. This was confirmed by an shRNA-mediated IGFBP2 knockdown, while maintaining MACC1 activity. Although IGFBP2 displayed an attenuated platelet activation potential, obviously by scavenging IGF-I as a platelet costimulatory mediator, the MACC1/IGFBP2 axis did not affect the thrombin formation potential of the cells. Furthermore, the IGFBP2/MACC1-driven cell migration and invasiveness was further accelerated by platelets. The key role of IGFBP2 for the metastatic spread in vivo was confirmed in a xenograft mouse model. Data provide evidence for IGFBP2 as a downstream functional component of MACC1-driven metastasis, linking these two accepted oncogenic biomarkers for the first time in a platelet context. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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21 pages, 26674 KiB

Open AccessArticle

The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner

by Henrike Hoermann, Irena Krueger, Nadine Maurus, Friedrich Reusswig, Yi Sun, Christina Kohlmorgen, Maria Grandoch, Jens W. Fischer and Margitta Elvers

Int. J. Mol. Sci. 2021, 22(22), 12168; https://doi.org/10.3390/ijms222212168 - 10 Nov 2021

Cited by 4 | Viewed by 2772

Abstract

Background: Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Different ECM proteins are known to initiate platelet adhesion and activation. In atherosclerotic mice, the small, leucine-rich proteoglycan biglycan is important for the regulation of thrombin activity via heparin cofactor II. However, nothing is known about the role of biglycan for hemostasis and thrombosis under nonatherosclerotic conditions. Methods: The role of biglycan for platelet adhesion and thrombus formation was investigated using a recombinant protein and biglycan knockout mice. Results: The present study identified biglycan as important ECM protein for the adhesion and activation of platelets, and the formation of three-dimensional thrombi under flow conditions. Platelet adhesion to immobilized biglycan induces the reorganization of the platelet cytoskeleton. Mechanistically, biglycan binds and activates the major collagen receptor glycoprotein (GP)VI, because reduced platelet adhesion to recombinant biglycan was observed when GPVI was blocked and enhanced tyrosine phosphorylation in a GPVI-dependent manner was observed when platelets were stimulated with biglycan. In vivo, the deficiency of biglycan resulted in reduced platelet adhesion to the injured carotid artery and prolonged bleeding times. Conclusions: Loss of biglycan in the vessel wall of mice but not in platelets led to reduced platelet adhesion at the injured carotid artery and prolonged bleeding times, suggesting a crucial role for biglycan as ECM protein that binds and activates platelets via GPVI upon vessel injury. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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18 pages, 2930 KiB

Open AccessArticle

Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment

by Bibian M. E. Tullemans, Alicia Veninga, Delia I. Fernandez, Maureen J. B. Aarts, Johannes A. Eble, Paola E. J. van der Meijden, Johan W. M. Heemskerk and Marijke J. E. Kuijpers

Int. J. Mol. Sci. 2021, 22(20), 11199; https://doi.org/10.3390/ijms222011199 - 18 Oct 2021

Cited by 8 | Viewed by 2682

Abstract

Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10–50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (>90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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20 pages, 3080 KiB

Open AccessArticle

Opposing Roles of GSK3α and GSK3β Phosphorylation in Platelet Function and Thrombosis

by Samantha F. Moore, Ejaife O. Agbani, Andreas Wersäll, Alastair W. Poole, Chris M. Williams, Xiaojuan Zhao, Yong Li, James L. Hutchinson, Roger W. Hunter and Ingeborg Hers

Int. J. Mol. Sci. 2021, 22(19), 10656; https://doi.org/10.3390/ijms221910656 - 30 Sep 2021

Cited by 15 | Viewed by 2896

Abstract

One of the mechanisms by which PI3 kinase can regulate platelet function is through phosphorylation of downstream substrates, including glycogen synthase kinase-3 (GSK3)α and GSK3β. Platelet activation results in the phosphorylation of an N-terminal serine residue in GSK3α (Ser21) and GSK3β (Ser9), which competitively inhibits substrate phosphorylation. However, the role of phosphorylation of these paralogs is still largely unknown. Here, we employed GSK3α/β phosphorylation-resistant mouse models to explore the role of this inhibitory phosphorylation in regulating platelet activation. Expression of phosphorylation-resistant GSK3α/β reduced thrombin-mediated platelet aggregation, integrin α_IIbβ₃ activation, and α-granule secretion, whereas platelet responses to the GPVI agonist collagen-related peptide (CRP-XL) were significantly enhanced. GSK3 single knock-in lines revealed that this divergence is due to differential roles of GSK3α and GSK3β phosphorylation in regulating platelet function. Expression of phosphorylation-resistant GSK3α resulted in enhanced GPVI-mediated platelet activation, whereas expression of phosphorylation-resistant GSK3β resulted in a reduction in PAR-mediated platelet activation and impaired in vitro thrombus formation under flow. Interestingly, the latter was normalised in double GSK3α/β KI mice, indicating that GSK3α KI can compensate for the impairment in thrombosis caused by GSK3β KI. In conclusion, our data indicate that GSK3α and GSK3β have differential roles in regulating platelet function. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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Review

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19 pages, 1224 KiB

Open AccessReview

Regulation of Key Antiplatelet Pathways by Bioactive Compounds with Minimal Bleeding Risk

by Eduardo Fuentes, Sergio Wehinger and Andrés Trostchansky

Int. J. Mol. Sci. 2021, 22(22), 12380; https://doi.org/10.3390/ijms222212380 - 17 Nov 2021

Cited by 8 | Viewed by 2752

Abstract

Cardiovascular disease is strongly influenced by platelet activation. Platelet activation and thrombus formation at atherosclerotic plaque rupture sites is a dynamic process regulated by different signaling networks. Therefore, there are now focused efforts to search for novel bioactive compounds which target receptors and pathways in the platelet activation process while preserving normal hemostatic function. The antiplatelet activity of numerous fruits and vegetables and their multiple mechanisms of action have recently been highlighted. In this review, we review the antiplatelet actions of bioactive compounds via key pathways (protein disulfide isomerase, mitogen-activated protein kinases, mitochondrial function, cyclic adenosine monophosphate, Akt, and shear stress-induced platelet aggregation) with no effects on bleeding time. Therefore, targeting these pathways might lead to the development of effective antiplatelet strategies that do not increase the risk of bleeding. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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21 pages, 1519 KiB

Open AccessReview

Molecular Proteomics and Signalling of Human Platelets in Health and Disease

by Jingnan Huang, Pengyu Zhang, Fiorella A. Solari, Albert Sickmann, Angel Garcia, Kerstin Jurk and Johan W. M. Heemskerk

Int. J. Mol. Sci. 2021, 22(18), 9860; https://doi.org/10.3390/ijms22189860 - 13 Sep 2021

Cited by 25 | Viewed by 5386

Abstract

Platelets are small anucleate blood cells that play vital roles in haemostasis and thrombosis, besides other physiological and pathophysiological processes. These roles are tightly regulated by a complex network of signalling pathways. Mass spectrometry-based proteomic techniques are contributing not only to the identification and quantification of new platelet proteins, but also reveal post-translational modifications of these molecules, such as acetylation, glycosylation and phosphorylation. Moreover, target proteomic analysis of platelets can provide molecular biomarkers for genetic aberrations with established or non-established links to platelet dysfunctions. In this report, we review 67 reports regarding platelet proteomic analysis and signalling on a molecular base. Collectively, these provide detailed insight into the: (i) technical developments and limitations of the assessment of platelet (sub)proteomes; (ii) molecular protein changes upon ageing of platelets; (iii) complexity of platelet signalling pathways and functions in response to collagen, rhodocytin, thrombin, thromboxane A₂ and ADP; (iv) proteomic effects of endothelial-derived mediators such as prostacyclin and the anti-platelet drug aspirin; and (v) molecular protein changes in platelets from patients with congenital disorders or cardiovascular disease. However, sample sizes are still low and the roles of differentially expressed proteins are often unknown. Based on the practical and technical possibilities and limitations, we provide a perspective for further improvements of the platelet proteomic field. Full article

(This article belongs to the Special Issue The Role of Platelets in Human Health and Disease)

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