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New Concepts in Platelet Activation and Thrombus Formation

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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 July 2023) | Viewed by 10132

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Special Issue Editor

Dr. Nicholas Pugh

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Guest Editor

Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, UK
Interests: zinc; platelets; zinc homeostasis; haemostasis; wound healing; zinc signalling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Platelets are the principal cellular determinants for both haemostasis following vascular injury, and for pathogenic thrombosis during adverse cardiovascular events. The exposure of subendothelial proteins permits platelet adhesion under conditions of shear stress. Signalling processes subsequently mediate platelet activation, which is characterised by platelet degranulation, shape change, and aggregation, leading to thrombus formation.

Platelet activation is regulated by engagement of receptors such as GpIb-V-IX, GpVI, CLEC-2, and integrin α_IIbβ₃ with cognate ligands, leading to intracellular signalling. Subsequent signalling via soluble platelet activators, including thrombin, ADP, and thromboxane, further contributes to activator processes. Recently, there has been growing interest in non-canonical regulators of platelet activation, such as chemokines, zinc, bacteria, and pathogen-associated molecular patterns (PAMPs).

This Special Issue focusses on recent studies that address the characterisation of new and established platelet activation mechanisms. It will present insights into exogenous stimuli that initiate platelet thrombus formation and will therefore highlight areas for new research directions that will influence the design of novel anti-thrombotics.

Dr. Nicholas Pugh
Guest Editor

Manuscript Submission Information

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

platelets
haemostasis
thrombosis
platelet activation
signalling

Published Papers (4 papers)

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Research

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17 pages, 2809 KiB

Open AccessArticle

Delineating Zinc Influx Mechanisms during Platelet Activation

by Sahithi J. Kuravi, Niaz S. Ahmed, Kirk A. Taylor, Emily M. Capes, Alex Bye, Amanda J. Unsworth, Jonathan M. Gibbins and Nicholas Pugh

Int. J. Mol. Sci. 2023, 24(14), 11689; https://doi.org/10.3390/ijms241411689 - 20 Jul 2023

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Abstract

Zinc (Zn²⁺) is released by platelets during a hemostatic response to injury. Extracellular zinc ([Zn²⁺]_o) initiates platelet activation following influx into the platelet cytosol. However, the mechanisms that permit Zn²⁺ influx are unknown. Fluctuations in intracellular zinc ([Zn²⁺]_i) were measured in fluozin-3-loaded platelets using fluorometry and flow cytometry. Platelet activation was assessed using light transmission aggregometry. The detection of phosphoproteins was performed by Western blotting. [Zn²⁺]_o influx and subsequent platelet activation were abrogated by blocking the sodium/calcium exchanged, TRP channels, and ZIP7. Cation store depletion regulated Zn²⁺ influx. [Zn²⁺]_o stimulation resulted in the phosphorylation of PKC substates, MLC, and β3 integrin. Platelet activation via GPVI or Zn²⁺ resulted in ZIP7 phosphorylation in a casein kinase 2-dependent manner and initiated elevations of [Zn²⁺]_i that were sensitive to the inhibition of Orai1, ZIP7, or IP₃R-mediated pathways. These data indicate that platelets detect and respond to changes in [Zn²⁺]_o via influx into the cytosol through TRP channels and the NCX exchanger. Platelet activation results in the externalization of ZIP7, which further regulates Zn²⁺ influx. Increases in [Zn²⁺]_i contribute to the activation of cation-dependent enzymes. Sensitivity of Zn²⁺ influx to thapsigargin indicates a store-operated pathway that we term store-operated Zn²⁺ entry (SOZE). These mechanisms may affect platelet behavior during thrombosis and hemostasis. Full article

(This article belongs to the Special Issue New Concepts in Platelet Activation and Thrombus Formation)

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Review

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14 pages, 1020 KiB

Open AccessReview

A Contemporary Review of Antiplatelet Therapies in Current Clinical Practice

by Sacchin Arockiam, Brittany Staniforth, Sacha Kepreotis, Annette Maznyczka and Heerajnarain Bulluck

Int. J. Mol. Sci. 2023, 24(13), 11132; https://doi.org/10.3390/ijms241311132 - 5 Jul 2023

Cited by 1 | Viewed by 2715

Abstract

Antiplatelet therapy plays a crucial role in a number of cardiovascular disorders. We currently have a range of antiplatelet agents in our armamentarium. In this review, we aim to summarise the common antiplatelet agents currently available, and their use in clinic practice. We not only highlight recent trials exploring antiplatelet therapy in atherosclerotic cardiovascular disease, but also in trials related to transcatheter aortic valve implantation and coronavirus disease 2019. Inevitably, the antithrombotic benefits of these drugs are accompanied by an increase in bleeding complications. Therefore, an individualised approach to weighing each patient’s thrombotic risk versus bleeding risk is imperative, in order to improve clinical outcomes. Full article

(This article belongs to the Special Issue New Concepts in Platelet Activation and Thrombus Formation)

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15 pages, 1270 KiB

Open AccessReview

Role of Nitric Oxide in Megakaryocyte Function

by Amir Asgari and Paul Jurasz

Int. J. Mol. Sci. 2023, 24(9), 8145; https://doi.org/10.3390/ijms24098145 - 2 May 2023

Cited by 1 | Viewed by 1748

Abstract

Megakaryocytes are the main members of the hematopoietic system responsible for regulating vascular homeostasis through their progeny platelets, which are generally known for maintaining hemostasis. Megakaryocytes are characterized as large polyploid cells that reside in the bone marrow but may also circulate in the vasculature. They are generated directly or through a multi-lineage commitment step from the most primitive progenitor or Hematopoietic Stem Cells (HSCs) in a process called “megakaryopoiesis”. Immature megakaryocytes enter a complicated development process defined as “thrombopoiesis” that ultimately results in the release of extended protrusions called proplatelets into bone marrow sinusoidal or lung microvessels. One of the main mediators that play an important modulatory role in hematopoiesis and hemostasis is nitric oxide (NO), a free radical gas produced by three isoforms of nitric oxide synthase within the mammalian cells. In this review, we summarize the effect of NO and its signaling on megakaryopoiesis and thrombopoiesis under both physiological and pathophysiological conditions. Full article

(This article belongs to the Special Issue New Concepts in Platelet Activation and Thrombus Formation)

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15 pages, 1405 KiB

Open AccessReview

Aspirin Resistance in Vascular Disease: A Review Highlighting the Critical Need for Improved Point-of-Care Testing and Personalized Therapy

by Hamzah Khan, Omar Kanny, Muzammil H. Syed and Mohammad Qadura

Int. J. Mol. Sci. 2022, 23(19), 11317; https://doi.org/10.3390/ijms231911317 - 26 Sep 2022

Cited by 10 | Viewed by 3605

Abstract

Aspirin resistance describes a phenomenon where patients receiving aspirin therapy do not respond favorably to treatment, and is categorized by continued incidence of adverse cardiovascular events and/or the lack of reduced platelet reactivity. Studies demonstrate that one in four patients with vascular disease are resistant to aspirin therapy, placing them at an almost four-fold increased risk of major adverse limb and adverse cardiovascular events. Despite the increased cardiovascular risk incurred by aspirin resistant patients, strategies to diagnose or overcome this resistance are yet to be clinically validated and integrated. Currently, five unique laboratory assays have shown promise for aspirin resistance testing: Light transmission aggregometry, Platelet Function Analyzer-100, Thromboelastography, Verify Now, and Platelet Works. Newer antiplatelet therapies such as Plavix and Ticagrelor have been tested as an alternative to overcome aspirin resistance (used both in combination with aspirin and alone) but have not proven to be superior to aspirin alone. A recent breakthrough discovery has demonstrated that rivaroxaban, an anticoagulant which functions by inhibiting active Factor X when taken in combination with aspirin, improves outcomes in patients with vascular disease. Current studies are determining how this new regime may benefit those who are considered aspirin resistant. Full article

(This article belongs to the Special Issue New Concepts in Platelet Activation and Thrombus Formation)

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