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Special Issue "Mechanisms of Platelet Thrombus Formation"

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 2017).

Special Issue Editor

Guest Editor
Prof. Dr. Denise Jackson Website E-Mail
Discipline Leader and Program Leader of Laboratory Medicine, BP147 Program Co-ordinator, Head of Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, PO Box 71, Bundoora, Victoria 3083, Australia

Special Issue Information

Dear Colleagues,

Platelets are normally free flowing in a blood vessel. However, in the event of vessel injury or disease such as atherosclerotic plaques, platelets will initially tether, via exposed extracellular matrix ligands with respective platelet receptors, then adhesive events occur, followed by activation through signaling events. These inside out signaling events lead to the conversion of the major platelet integrin alphaIIbbeta3 from a resting to an activated state, where it will bind its natural ligands, including fibrinogen, to create stable platelet aggregates. The numerous steps involved in platelet thrombus formation are regulated by different receptors, ligands, signaling molecules, rheological biomechanical forces, and soluble agonist dependent mechanisms. These events regulate not only thrombus growth and stability but also the propagation of blood clots formed.

Prof. Dr. Denise Jackson
Guest Editor

Manuscript Submission Information

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Keywords

  • platelet adhesion
  • platelet aggregation
  • tissue factor bearing microparticles
  • thrombus growth
  • thrombus stability
  • platelet tethering
  • platelet activation
  • propagation of thrombus formation
  • rheological biomechanical platelet aggregation
  • soluble agonist dependent mechanisms

Published Papers (6 papers)

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Research

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Open AccessArticle
Pancreatic Cancer-Induced Neutrophil Extracellular Traps: A Potential Contributor to Cancer-Associated Thrombosis
Int. J. Mol. Sci. 2017, 18(3), 487; https://doi.org/10.3390/ijms18030487 - 24 Feb 2017
Cited by 26
Abstract
Pancreatic cancer (PaCa) is a highly metastatic cancer, and patients are at high risk of developing venous thromboembolism (VTE). Neutrophil extracellular traps (NETs) have been associated with cancer metastasis and cancer-associated thrombosis, but the ability of cancer to stimulate NET release is not [...] Read more.
Pancreatic cancer (PaCa) is a highly metastatic cancer, and patients are at high risk of developing venous thromboembolism (VTE). Neutrophil extracellular traps (NETs) have been associated with cancer metastasis and cancer-associated thrombosis, but the ability of cancer to stimulate NET release is not known. The release of NETs has been shown to be a slow process and requires reactive oxygen species (ROS) production. Studies suggest that activated platelets are important mediators in the release. Here, we show that PaCa cells can stimulate the rapid release of NETs, independently of ROS production. We further assessed the role of platelets in PaCa-induced NETs and observed a trend of increased the NET release by PaCa-primed platelets. Additionally, NETs promoted thrombus formation under venous shear stress ex vivo. Taken together, our results suggest that PaCa-induced NETs can contribute to the high risk of venous thromboembolism development in PaCa patients, and reveal NETs as a potential therapeutic target. Full article
(This article belongs to the Special Issue Mechanisms of Platelet Thrombus Formation)
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Open AccessArticle
Uridine Triphosphate Thio Analogues Inhibit Platelet P2Y12 Receptor and Aggregation
Int. J. Mol. Sci. 2017, 18(2), 269; https://doi.org/10.3390/ijms18020269 - 29 Jan 2017
Cited by 2
Abstract
Platelet P2Y12 is an important adenosine diphosphate (ADP) receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio analogues of uridine triphosphate (UTP) on ADP-induced platelet [...] Read more.
Platelet P2Y12 is an important adenosine diphosphate (ADP) receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma, we demonstrate that UTP inhibits P2Y12 but not P2Y1 receptors and antagonises 10 µM ADP-induced platelet aggregation in a concentration-dependent manner with an IC50 value of ~250 °µM. An eight-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC50 of 30 µM. The 4-thio analogue (4S-UTP) with an IC50 of 7.5 µM was 33-fold more effective. A three-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4S- position. A complete loss of inhibition was observed with thio-modification of the γ phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y12 receptor was verified by P2Y12 receptor binding and cyclic AMP (cAMP) assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y12 receptor antagonists that may be useful for therapeutic intervention. Full article
(This article belongs to the Special Issue Mechanisms of Platelet Thrombus Formation)
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Review

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Open AccessReview
Importance of Endogenous Fibrinolysis in Platelet Thrombus Formation
Int. J. Mol. Sci. 2017, 18(9), 1850; https://doi.org/10.3390/ijms18091850 - 25 Aug 2017
Cited by 4
Abstract
The processes of thrombosis and coagulation are finely regulated by endogenous fibrinolysis maintaining healthy equilibrium. When the balance is altered in favour of platelet activation and/or coagulation, or if endogenous fibrinolysis becomes less efficient, pathological thrombosis can occur. Arterial thrombosis remains a major [...] Read more.
The processes of thrombosis and coagulation are finely regulated by endogenous fibrinolysis maintaining healthy equilibrium. When the balance is altered in favour of platelet activation and/or coagulation, or if endogenous fibrinolysis becomes less efficient, pathological thrombosis can occur. Arterial thrombosis remains a major cause of morbidity and mortality in the world despite advances in medical therapies. The role endogenous fibrinolysis in the pathogenesis of arterial thrombosis has gained increasing attention in recent years as it presents novel ways to prevent and treat existing diseases. In this review article, we discuss the role of endogenous fibrinolysis in platelet thrombus formation, methods of measurement of fibrinolytic activity, its role in predicting cardiovascular diseases and clinical outcomes and future directions. Full article
(This article belongs to the Special Issue Mechanisms of Platelet Thrombus Formation)
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Open AccessReview
Platelet Aggregometry Testing: Molecular Mechanisms, Techniques and Clinical Implications
Int. J. Mol. Sci. 2017, 18(8), 1803; https://doi.org/10.3390/ijms18081803 - 18 Aug 2017
Cited by 10
Abstract
Platelets play a fundamental role in normal hemostasis, while their inherited or acquired dysfunctions are involved in a variety of bleeding disorders or thrombotic events. Several laboratory methodologies or point-of-care testing methods are currently available for clinical and experimental settings. These methods describe [...] Read more.
Platelets play a fundamental role in normal hemostasis, while their inherited or acquired dysfunctions are involved in a variety of bleeding disorders or thrombotic events. Several laboratory methodologies or point-of-care testing methods are currently available for clinical and experimental settings. These methods describe different aspects of platelet function based on platelet aggregation, platelet adhesion, the viscoelastic properties during clot formation, the evaluation of thromboxane metabolism or certain flow cytometry techniques. Platelet aggregometry is applied in different clinical settings as monitoring response to antiplatelet therapies, the assessment of perioperative bleeding risk, the diagnosis of inherited bleeding disorders or in transfusion medicine. The rationale for platelet function-driven antiplatelet therapy was based on the result of several studies on patients undergoing percutaneous coronary intervention (PCI), where an association between high platelet reactivity despite P2Y12 inhibition and ischemic events as stent thrombosis or cardiovascular death was found. However, recent large scale randomized, controlled trials have consistently failed to demonstrate a benefit of personalised antiplatelet therapy based on platelet function testing. Full article
(This article belongs to the Special Issue Mechanisms of Platelet Thrombus Formation)
Open AccessReview
Pannexin- and Connexin-Mediated Intercellular Communication in Platelet Function
Int. J. Mol. Sci. 2017, 18(4), 850; https://doi.org/10.3390/ijms18040850 - 17 Apr 2017
Cited by 6
Abstract
The three major blood cell types, i.e., platelets, erythrocytes and leukocytes, are all produced in the bone marrow. While red blood cells are the most numerous and white cells are the largest, platelets are small fragments and account for a minor part of [...] Read more.
The three major blood cell types, i.e., platelets, erythrocytes and leukocytes, are all produced in the bone marrow. While red blood cells are the most numerous and white cells are the largest, platelets are small fragments and account for a minor part of blood volume. However, platelets display a crucial function by preventing bleeding. Upon vessel wall injury, platelets adhere to exposed extracellular matrix, become activated, and form a platelet plug preventing hemorrhagic events. However, when platelet activation is exacerbated, as in rupture of an atherosclerotic plaque, the same mechanism may lead to acute thrombosis causing major ischemic events such as myocardial infarction or stroke. In the past few years, major progress has been made in understanding of platelet function modulation. In this respect, membrane channels formed by connexins and/or pannexins are of particular interest. While it is still not completely understood whether connexins function as hemichannels or gap junction channels to inhibit platelet aggregation, there is clear-cut evidence for a specific implication of pannexin1 channels in collagen-induced aggregation. The focus of this review is to summarize current knowledge of the role of connexins and pannexins in platelet aggregation and to discuss possible pharmacological approaches along with their limitations and future perspectives for new potential therapies. Full article
(This article belongs to the Special Issue Mechanisms of Platelet Thrombus Formation)
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Other

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Open AccessBrief Report
Syk Activity Is Dispensable for Platelet GP1b-IX-V Signaling
Int. J. Mol. Sci. 2017, 18(6), 1238; https://doi.org/10.3390/ijms18061238 - 09 Jun 2017
Cited by 3
Abstract
The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. [...] Read more.
The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. However, there have been conflicting reports regarding the role of Syk in GP1b signaling. In this study, we sought to resolve these conflicting reports and clarify the role of Syk in VWF-induced platelet activation. The inhibition of Syk with the selective Syk inhibitors, OXSI-2 and PRT-060318, did not inhibit VWF-induced platelet adhesion, agglutination, aggregation, or secretion. In contrast, platelets stimulated with the Glycoprotein VI (GPVI) agonist, collagen-related peptide (CRP), failed to cause any aggregation or secretion in presence of the Syk inhibitors. Furthermore, GP1b-induced platelet signaling was unaffected in the presence of Syk inhibitors, but GPVI-induced signaling was abolished under similar conditions. Thus, we conclude that Syk kinase activity does not play any functional role downstream of GP1b-mediated platelet activation. Full article
(This article belongs to the Special Issue Mechanisms of Platelet Thrombus Formation)
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