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Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation

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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 44144

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Special Issue Editors

Dr. Kerstin Jurk

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Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
Interests: coagulation; platelets; haemostasis; omics; signal transduction; thrombo-inflammation; thrombosis; vessel wall
Special Issues, Collections and Topics in MDPI journals

Dr. Marijke J.E. Kuijpers

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Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
Interests: coagulation; platelets; haemostasis; omics; signal transduction; thrombo-inflammation; thrombosis; vessel wall
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Johan W. M. Heemskerk

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Guest Editor

Synapse Research Institute, Kon. Emmaplein 7, 6214 AC Maastricht, The Netherlands
Interests: coagulation; platelets; haemostasis; omics; signal transduction; thrombo-inflammation; thrombosis; vessel wall
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the present decade, we are seeing a rapid increase of available genetics and multiomics information on components of the human and mammalian circulation, involved in haemostasis, athero- and venous thrombosis and thrombo-inflammation. In this Special Issue, we aim to collect state-of-the-art scientific contributions (reviews and original articles) that provide novel molecular insights into the complex interactions in the blood and the vessel wall in physiological and pathophysiological settings. These include molecular mechanisms contributing to coagulation, platelet activation, leukocyte, erythrocyte and vascular cell functions, extracellular vesicles and inter-cellular cross-talk both in vitro and in vivo. Clinical papers without defined molecular mechanisms are not solicited.

Dr. Kerstin Jurk
Dr. Marijke J.E. Kuijpers
Prof. Dr. Johan W.M. Heemskerk
Guest Editors

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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

coagulation
inflammation
leukocytes
platelets
proteomics
red blood cells
vessel wall
extracellular vesicles

Related Special Issue

Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation 2.0 in International Journal of Molecular Sciences (21 articles)

Published Papers (13 papers)

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Editorial

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4 pages, 196 KiB

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Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation

by Marijke J. E. Kuijpers, Johan W. M. Heemskerk and Kerstin Jurk

Int. J. Mol. Sci. 2022, 23(10), 5825; https://doi.org/10.3390/ijms23105825 - 23 May 2022

Cited by 4 | Viewed by 2854

Abstract

In the present decade, we are seeing a rapid increase in available genetics and multiomics information on blood and vascular components of the human and mammalian circulation, involved in haemostasis, athero- and venous thrombosis, and thrombo-inflammation [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

Research

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18 pages, 4103 KiB

Open AccessArticle

Formation of Neutrophil Extracellular Traps by Reduction of Cellular Cholesterol Is Independent of Oxygen and HIF-1α

by Timo Henneck, AhmedElmontaser Mergani, Sabrina Clever, Anna E. Seidler, Graham Brogden, Sandra Runft, Wolfgang Baumgärtner, Katja Branitzki-Heinemann and Maren von Köckritz-Blickwede

Int. J. Mol. Sci. 2022, 23(6), 3195; https://doi.org/10.3390/ijms23063195 - 16 Mar 2022

Cited by 6 | Viewed by 2227

Abstract

Formation of neutrophil extracellular traps (NETs) is a two-faced innate host defense mechanism, which, on the one hand, can counteract microbial infections, but on the other hand, can contribute to massive detrimental effects on the host. Cholesterol depletion from the cellular membrane by Methyl-β-cyclodextrin (MβCD) is known as one of the processes initiating NET formation. Since neutrophils mainly act in an inflammatory environment with decreased, so-called hypoxic, oxygen conditions, we aimed to study the effect of oxygen and the oxygen stress regulator hypoxia-inducible factor (HIF)-1α on cholesterol-dependent NET formation. Thus, murine bone marrow-derived neutrophils from wild-type and HIF-knockout mice or human neutrophils were stimulated with MβCD under normoxic (21% O₂) compared to hypoxic (1% O₂) conditions, and the formation of NETs were studied by immunofluorescence microscopy. We found significantly induced NET formation after treatment with MβCD in murine neutrophils derived from wild-type as well as HIF-1α KO mice at both hypoxic (1% O₂) as well as normoxic (21% O₂) conditions. Similar observations were made in freshly isolated human neutrophils after stimulation with MβCD or statins, which block the HMG-CoA reductase as the key enzyme in the cholesterol metabolism. HPLC was used to confirm the reduction of cholesterol in treated neutrophils. In summary, we were able to show that NET formation via MβCD or statin-treatment is oxygen and HIF-1α independent. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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18 pages, 3043 KiB

Open AccessArticle

The Platelet Collagen Receptor GPVI Is Cleaved by Tspan15/ADAM10 and Tspan33/ADAM10 Molecular Scissors

by Chek Ziu Koo, Alexandra L. Matthews, Neale Harrison, Justyna Szyroka, Bernhard Nieswandt, Elizabeth E. Gardiner, Natalie S. Poulter and Michael G. Tomlinson

Int. J. Mol. Sci. 2022, 23(5), 2440; https://doi.org/10.3390/ijms23052440 - 23 Feb 2022

Cited by 8 | Viewed by 2834

Abstract

The platelet-activating collagen receptor GPVI represents the focus of clinical trials as an antiplatelet target for arterial thrombosis, and soluble GPVI is a plasma biomarker for several human diseases. A disintegrin and metalloproteinase 10 (ADAM10) acts as a ‘molecular scissor’ that cleaves the extracellular region from GPVI and many other substrates. ADAM10 interacts with six regulatory tetraspanin membrane proteins, Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 and Tspan33, which are collectively termed the TspanC8s. These are emerging as regulators of ADAM10 substrate specificity. Human platelets express Tspan14, Tspan15 and Tspan33, but which of these regulates GPVI cleavage remains unknown. To address this, CRISPR/Cas9 knockout human cell lines were generated to show that Tspan15 and Tspan33 enact compensatory roles in GPVI cleavage, with Tspan15 bearing the more important role. To investigate this mechanism, a series of Tspan15 and GPVI mutant expression constructs were designed. The Tspan15 extracellular region was found to be critical in promoting GPVI cleavage, and appeared to achieve this by enabling ADAM10 to access the cleavage site at a particular distance above the membrane. These findings bear implications for the regulation of cleavage of other ADAM10 substrates, and provide new insights into post-translational regulation of the clinically relevant GPVI protein. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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20 pages, 5012 KiB

Open AccessArticle

Structure-Based Cyclic Glycoprotein Ibα-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear

by Johana Hrdinova, Delia I. Fernández, Bogac Ercig, Bibian M. E. Tullemans, Dennis P. L. Suylen, Stijn M. Agten, Kerstin Jurk, Tilman M. Hackeng, Karen Vanhoorelbeke, Jan Voorberg, Chris P. M. Reutelingsperger, Kanin Wichapong, Johan W. M. Heemskerk and Gerry A. F. Nicolaes

Int. J. Mol. Sci. 2022, 23(4), 2046; https://doi.org/10.3390/ijms23042046 - 12 Feb 2022

Cited by 10 | Viewed by 2133

Abstract

The plasmatic von Willebrand factor (VWF) circulates in a compact form unable to bind platelets. Upon shear stress, the VWF A1 domain is exposed, allowing VWF-binding to platelet glycoprotein Ib-V-IX (GPIbα chain). For a better understanding of the role of this interaction in cardiovascular disease, molecules are needed to specifically interfere with the opened VWF A1 domain interaction with GPIbα. Therefore, we in silico designed and chemically synthetized stable cyclic peptides interfering with the platelet-binding of the VWF A1 domain per se or complexed with botrocetin. Selected peptides (26–34 amino acids) with the lowest-binding free energy were: the monocyclic mono- vOn Willebrand factoR-GPIbα InTerference (ORbIT) peptide and bicyclic bi-ORbIT peptide. Interference of the peptides in the binding of VWF to GPIb-V-IX interaction was retained by flow cytometry in comparison with the blocking of anti-VWF A1 domain antibody CLB-RAg35. In collagen and VWF-dependent whole-blood thrombus formation at a high shear rate, CLB-RAg35 suppressed stable platelet adhesion as well as the formation of multilayered thrombi. Both peptides phenotypically mimicked these changes, although they were less potent than CLB-RAg35. The second-round generation of an improved peptide, namely opt-mono-ORbIT (28 amino acids), showed an increased inhibitory activity under flow. Accordingly, our structure-based design of peptides resulted in physiologically effective peptide-based inhibitors, even for convoluted complexes such as GPIbα-VWF A1. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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15 pages, 3307 KiB

Open AccessArticle

Heparin-Functionalized Adsorbents Eliminate Central Effectors of Immunothrombosis, including Platelet Factor 4, High-Mobility Group Box 1 Protein and Histones

by Marie Ebeyer-Masotta, Tanja Eichhorn, René Weiss, Vladislav Semak, Lucia Lauková, Michael B. Fischer and Viktoria Weber

Int. J. Mol. Sci. 2022, 23(3), 1823; https://doi.org/10.3390/ijms23031823 - 05 Feb 2022

Cited by 13 | Viewed by 4395

Abstract

Inflammation and thrombosis are closely intertwined in numerous disorders, including ischemic events and sepsis, as well as coronavirus disease 2019 (COVID-19). Thrombotic complications are markers of disease severity in both sepsis and COVID-19 and are associated with multiorgan failure and increased mortality. Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of neutrophil extracellular traps (NETs) and release further effectors of immunothrombosis, including platelet factor 4 (PF4/CXCL4) and high-mobility box 1 protein (HMGB1). Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. Here, we provide evidence that adsorbents functionalized with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. We propose that this elimination of central effectors of immunothrombosis, rather than direct binding of pathogens, could be of clinical relevance for mitigating thrombotic complications in sepsis or COVID-19 using heparin-functionalized adsorbents. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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15 pages, 3802 KiB

Open AccessArticle

Role of Tyrosine Kinase Syk in Thrombus Stabilisation at High Shear

by Gina Perrella, Samantha J. Montague, Helena C. Brown, Lourdes Garcia Quintanilla, Alexandre Slater, David Stegner, Mark Thomas, Johan W. M. Heemskerk and Steve P. Watson

Int. J. Mol. Sci. 2022, 23(1), 493; https://doi.org/10.3390/ijms23010493 - 01 Jan 2022

Cited by 7 | Viewed by 2330

Abstract

Understanding the pathways involved in the formation and stability of the core and shell regions of a platelet-rich arterial thrombus may result in new ways to treat arterial thrombosis. The distinguishing feature between these two regions is the absence of fibrin in the shell which indicates that in vitro flow-based assays over thrombogenic surfaces, in the absence of coagulation, can be used to resemble this region. In this study, we have investigated the contribution of Syk tyrosine kinase in the stability of platelet aggregates (or thrombi) formed on collagen or atherosclerotic plaque homogenate at arterial shear (1000 s⁻¹). We show that post-perfusion of the Syk inhibitor PRT-060318 over preformed thrombi on both surfaces enhances thrombus breakdown and platelet detachment. The resulting loss of thrombus stability led to a reduction in thrombus contractile score which could be detected as early as 3 min after perfusion of the Syk inhibitor. A similar loss of thrombus stability was observed with ticagrelor and indomethacin, inhibitors of platelet adenosine diphosphate (ADP) receptor and thromboxane A₂ (TxA₂), respectively, and in the presence of the Src inhibitor, dasatinib. In contrast, the Btk inhibitor, ibrutinib, causes only a minor decrease in thrombus contractile score. Weak thrombus breakdown is also seen with the blocking GPVI nanobody, Nb21, which indicates, at best, a minor contribution of collagen to the stability of the platelet aggregate. These results show that Syk regulates thrombus stability in the absence of fibrin in human platelets under flow and provide evidence that this involves pathways additional to activation of GPVI by collagen. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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19 pages, 6651 KiB

Open AccessArticle

Temporal Roles of Platelet and Coagulation Pathways in Collagen- and Tissue Factor-Induced Thrombus Formation

by Stefano Navarro, David Stegner, Bernhard Nieswandt, Johan W. M. Heemskerk and Marijke J. E. Kuijpers

Int. J. Mol. Sci. 2022, 23(1), 358; https://doi.org/10.3390/ijms23010358 - 29 Dec 2021

Cited by 18 | Viewed by 2466

Abstract

In hemostasis and thrombosis, the complex process of thrombus formation involves different molecular pathways of platelet and coagulation activation. These pathways are considered as operating together at the same time, but this has not been investigated. The objective of our study was to elucidate the time-dependency of key pathways of thrombus and clot formation, initiated by collagen and tissue factor surfaces, where coagulation is triggered via the extrinsic route. Therefore, we adapted a microfluidics whole-blood assay with the Maastricht flow chamber to acutely block molecular pathways by pharmacological intervention at desired time points. Application of the technique revealed crucial roles of glycoprotein VI (GPVI)-induced platelet signaling via Syk kinase as well as factor VIIa-induced thrombin generation, which were confined to the first minutes of thrombus buildup. A novel anti-GPVI Fab EMF-1 was used for this purpose. In addition, platelet activation with the protease-activating receptors 1/4 (PAR1/4) and integrin αIIbβ3 appeared to be prolongedly active and extended to later stages of thrombus and clot formation. This work thereby revealed a more persistent contribution of thrombin receptor-induced platelet activation than of collagen receptor-induced platelet activation to the thrombotic process. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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15 pages, 20399 KiB

Open AccessArticle

PCSK9 Induces Tissue Factor Expression by Activation of TLR4/NFkB Signaling

by Valentina Scalise, Chiara Sanguinetti, Tommaso Neri, Silvana Cianchetti, Michele Lai, Vittoria Carnicelli, Alessandro Celi and Roberto Pedrinelli

Int. J. Mol. Sci. 2021, 22(23), 12640; https://doi.org/10.3390/ijms222312640 - 23 Nov 2021

Cited by 27 | Viewed by 3466

Abstract

Proprotein convertase subtilisin kexin 9 (PCSK9) increases LDL cholesterol (C) concentration by accelerating the hepatic degradation of the LDL receptor (R) thus promoting atherogenesis. The molecule, however, also exerts proinflammatory effects independent of circulating LDL-C by enhancing local cytokine production and activation of NFkB, a process that might involve Toll-like receptor 4 (TLR4), a crucial component of the innate immunity system. Tissue factor (TF), a glycoprotein which plays an essential role in coagulation and inflammation, is rapidly induced by circulating monocytes stimulated by proinflammatory agents through NFkB-dependent mechanisms. The aims of our study were (1) to assess whether PCSK9 may induce monocytic TF expression and (2) to evaluate whether the TLR4/NFkB signaling pathway may contribute to that effect. Experiments were carried out in peripheral blood mononuclear cells (PBMCs), THP-1 cells, and HEK293 cells transfected with plasmids encoding the human TLR4 complex. PCSK9 increased procoagulant activity (PCA), mRNA and TF protein expression in both PBMCs and THP-1 cultures. Pre-treatment with inhibitors of TLR4/NFkB signaling such as LPS-RS, CLI-095, and BAY 11-7082, downregulated PCSK9-induced TF expression. A similar effect was obtained by incubating cell cultures with anti-PCSK9 human monoclonal antibody. In TLR4-HEK293 cells, PCSK9 activated the TLR4/NFkB signaling pathway to an extent comparable to LPS, the specific agonist of TLR4s and quantitative confocal microscopy documented the colocalization of PCSK9 and TLR4s. In conclusion, PCSK9 induces TF expression through activation of TLR4/NFkB signaling. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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9 pages, 2851 KiB

Open AccessArticle

Early Adventitial Activation and Proliferation in a Mouse Model of Arteriovenous Stenosis: Opportunities for Intervention

by Jenq-Shyong Chan, Yang Wang, Virgilius Cornea, Prabir Roy-Chaudhury and Begoña Campos

Int. J. Mol. Sci. 2021, 22(22), 12285; https://doi.org/10.3390/ijms222212285 - 13 Nov 2021

Cited by 3 | Viewed by 1556

Abstract

Background: Arteriovenous fistula (AVF) stenosis remains an important cause of AVF maturation failure, for which there are currently no effective therapies. We examined the pattern and phenotype of cellular proliferation at different timepoints in a mouse model characterized by a peri-anastomotic AVF stenosis. Methods: Standard immunohistochemical analyses for cellular proliferation and macrophage infiltration were performed at 2, 7 and 14 d on our validated mouse model of AVF stenosis to study the temporal profile, geographical location and cellular phenotype of proliferating and infiltrating cells in this model. Results: Adventitial proliferation and macrophage infiltration (into the adventitia) began at 2 d, peaked at 7 d and then declined over time. Surprisingly, there was minimal macrophage infiltration or proliferation in the neointimal region at either 7 or 14 d, although endothelial cell proliferation increased rapidly between 2 d and 7 d, and peaked at 14 d. Conclusions: Early and rapid macrophage infiltration and cellular proliferation within the adventitia could play an important role in the downstream pathways of both neointimal hyperplasia and inward or outward remodelling. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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Review

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30 pages, 1602 KiB

Open AccessReview

Beyond Hemostasis: Platelet Innate Immune Interactions and Thromboinflammation

by Jonathan Mandel, Martina Casari, Maria Stepanyan, Alexey Martyanov and Carsten Deppermann

Int. J. Mol. Sci. 2022, 23(7), 3868; https://doi.org/10.3390/ijms23073868 - 31 Mar 2022

Cited by 53 | Viewed by 8754

Abstract

There is accumulating evidence that platelets play roles beyond their traditional functions in thrombosis and hemostasis, e.g., in inflammatory processes, infection and cancer, and that they interact, stimulate and regulate cells of the innate immune system such as neutrophils, monocytes and macrophages. In this review, we will focus on platelet activation in hemostatic and inflammatory processes, as well as platelet interactions with neutrophils and monocytes/macrophages. We take a closer look at the contributions of major platelet receptors GPIb, α_IIbβ₃, TLT-1, CLEC-2 and Toll-like receptors (TLRs) as well as secretions from platelet granules on platelet–neutrophil aggregate and neutrophil extracellular trap (NET) formation in atherosclerosis, transfusion-related acute lung injury (TRALI) and COVID-19. Further, we will address platelet–monocyte and macrophage interactions during cancer metastasis, infection, sepsis and platelet clearance. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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28 pages, 3124 KiB

Open AccessReview

Mechanisms Underlying Dichotomous Procoagulant COAT Platelet Generation—A Conceptual Review Summarizing Current Knowledge

by Lucas Veuthey, Alessandro Aliotta, Debora Bertaggia Calderara, Cindy Pereira Portela and Lorenzo Alberio

Int. J. Mol. Sci. 2022, 23(5), 2536; https://doi.org/10.3390/ijms23052536 - 25 Feb 2022

Cited by 11 | Viewed by 2930

Abstract

Procoagulant platelets are a subtype of activated platelets that sustains thrombin generation in order to consolidate the clot and stop bleeding. This aspect of platelet activation is gaining more and more recognition and interest. In fact, next to aggregating platelets, procoagulant platelets are key regulators of thrombus formation. Imbalance of both subpopulations can lead to undesired thrombotic or bleeding events. COAT platelets derive from a common pro-aggregatory phenotype in cells capable of accumulating enough cytosolic calcium to trigger specific pathways that mediate the loss of their aggregating properties and the development of new adhesive and procoagulant characteristics. Complex cascades of signaling events are involved and this may explain why an inter-individual variability exists in procoagulant potential. Nowadays, we know the key agonists and mediators underlying the generation of a procoagulant platelet response. However, we still lack insight into the actual mechanisms controlling this dichotomous pattern (i.e., procoagulant versus aggregating phenotype). In this review, we describe the phenotypic characteristics of procoagulant COAT platelets, we detail the current knowledge on the mechanisms of the procoagulant response, and discuss possible drivers of this dichotomous diversification, in particular addressing the impact of the platelet environment during in vivo thrombus formation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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21 pages, 5287 KiB

Open AccessReview

Role of Neutrophils and NETs in Animal Models of Thrombosis

by Estelle Carminita, Lydie Crescence, Laurence Panicot-Dubois and Christophe Dubois

Int. J. Mol. Sci. 2022, 23(3), 1411; https://doi.org/10.3390/ijms23031411 - 26 Jan 2022

Cited by 17 | Viewed by 4995

Abstract

Thrombosis is one of the major causes of mortality worldwide. Notably, it is not only implicated in cardiovascular diseases, such as myocardial infarction (MI), stroke, and pulmonary embolism (PE), but also in cancers. Understanding the cellular and molecular mechanisms involved in platelet thrombus formation is a major challenge for scientists today. For this purpose, new imaging technologies (such as confocal intravital microscopy, electron microscopy, holotomography, etc.) coupled with animal models of thrombosis (mouse, rat, rabbit, etc.) allow a better overview of this complex physiopathological process. Each of the cellular components is known to participate, including the subendothelial matrix, the endothelium, platelets, circulating cells, and, notably, neutrophils. Initially known as immune cells, neutrophils have been considered to be part of the landscape of thrombosis for more than a decade. They participate in this biological process through their expression of tissue factor (TF) and protein disulfide isomerase (PDI). Moreover, highly activated neutrophils are described as being able to release their DNA and thus form chromatin networks known as “neutrophil extracellular traps” (NETs). Initially, described as “dead sacrifices for a good cause” that prevent the dissemination of bacteria in the body, NETs have also been studied in several human pathologies, such as cardiovascular and respiratory diseases. Many articles suggest that they are involved in platelet thrombus formation and the activation of the coagulation cascade. This review presents the models of thrombosis in which neutrophils and NETs are involved and describes their mechanisms of action. We have even highlighted the medical diagnostic advances related to this research. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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Other

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15 pages, 3289 KiB

Open AccessBrief Report

Rac Inhibition Causes Impaired GPVI Signalling in Human Platelets through GPVI Shedding and Reduction in PLCγ2 Phosphorylation

by Raluca A. I. Neagoe, Elizabeth E. Gardiner, David Stegner, Bernhard Nieswandt, Steve P. Watson and Natalie S. Poulter

Int. J. Mol. Sci. 2022, 23(7), 3746; https://doi.org/10.3390/ijms23073746 - 29 Mar 2022

Cited by 3 | Viewed by 1830

Abstract

Rac1 is a small Rho GTPase that is activated in platelets upon stimulation with various ligands, including collagen and thrombin, which are ligands for the glycoprotein VI (GPVI) receptor and the protease-activated receptors, respectively. Rac1-deficient murine platelets have impaired lamellipodia formation, aggregation, and reduced PLCγ2 activation, but not phosphorylation. The objective of our study is to investigate the role of Rac1 in GPVI-dependent human platelet activation and downstream signalling. Therefore, we used human platelets stimulated using GPVI agonists (collagen and collagen-related peptide) in the presence of the Rac1-specific inhibitor EHT1864 and analysed platelet activation, aggregation, spreading, protein phosphorylation, and GPVI clustering and shedding. We observed that in human platelets, the inhibition of Rac1 by EHT1864 had no significant effect on GPVI clustering on collagen fibres but decreased the ability of platelets to spread or aggregate in response to GPVI agonists. Additionally, in contrast to what was observed in murine Rac1-deficient platelets, EHT1864 enhanced GPVI shedding in platelets and reduced the phosphorylation levels of PLCγ2 following GPVI activation. In conclusion, Rac1 activity is required for both human and murine platelet activation in response to GPVI-ligands, but Rac1’s mode of action differs between the two species. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation)

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