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Platelet Activation 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 Immunology".

Deadline for manuscript submissions: 20 January 2025 | Viewed by 10670

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Dr. Demokritos Tsoukatos

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Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, 45110 Ioannina, Greece
Interests: platelet activating factor

Special Issue Information

Dear Colleagues,

Platelets are pieces of very large cells in the bone marrow called megakaryocytes. They help form blood clots to slow or stop bleeding and to help wounds heal. αIIbβ3, the major platelet integrin, plays a central role in haemostasis and thrombosis. Upon platelet activation, the conformation of αIIbβ3 changes allows fibrinogen binding and, subsequently, platelet aggregation.

YMESRADR, a peptide corresponding to the extracellular sequence 313-320 of αIIb, is also a potent platelet aggregation inhibitor which mimics the effect of a clasp between the head domains of αIIb and β3. Platelet preincubation with Pal-K-LEEDDEGE followed by YMESRADR showed synergistic inhibitory activity on platelet aggregation. Platelet incubation with threshold inhibitory concentrations of both peptides provoked almost total inhibition of aggregation. However, in contrast with the RGD peptide that enhances ERK phosphorylation and activation, the mixture of Pal-K-LEEDDEEGE and YMESRADR also inhibits ERK phosphorylation. It was suggested that the use of the intracellular inhibitor in combination with the extracellular peptide inhibitor, acting with a non-RGD-like mechanism, may provide an alternative pharmacological approach to antagonizing integrin αIIbβ3 activation.

In this Special Issue of IJMS, we will focus on molecular mechanisms underlying platelet response, biogenesis, activation, aggregation and function in human health and diseases. Research papers and reviews on the above-mentioned topics are particularly welcome.

Dr. Demokritos Tsoukatos
Guest Editor

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Keywords

integrin αΙΙbβ3
αIIb subunit
platelet aggregation
platelet activation
talin
peptide inhibitors

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Published Papers (7 papers)

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Research

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12 pages, 1045 KiB

Open AccessArticle

Differential Effect of Omega-3 Fatty Acids on Platelet Inhibition by Antiplatelet Drugs In Vitro

by Ioannis K. Koutsaliaris, Despoina Pantazi, Aikaterini N. Tsouka, Ourania Argyropoulou, Constantinos C. Tellis and Alexandros D. Tselepis

Int. J. Mol. Sci. 2024, 25(18), 10136; https://doi.org/10.3390/ijms251810136 - 21 Sep 2024

Viewed by 846

Abstract

The omega-3 polyunsaturated fatty acids (PUFAs) Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) exert multiple cardioprotective effects, influencing inflammation, platelet activation, endothelial function and lipid metabolism, besides their well-established triglyceride lowering properties. It is not uncommon for omega-3 PUFAs to be prescribed for hypertriglyceridemia, alongside antiplatelet therapy in cardiovascular disease (CVD) patients. In this regard, we studied the effect of EPA and DHA, in combination with antiplatelet drugs, in platelet aggregation and P-selectin and α_IIbβ₃ membrane expression. The antiplatelet drugs aspirin and triflusal, inhibitors of cyclooxygenase-1 (COX-1); ticagrelor, an inhibitor of the receptor P2Y₁₂; vorapaxar, an inhibitor of the PAR-1 receptor, were combined with DHA or EPA and evaluated against in vitro platelet aggregation induced by agonists arachidonic acid (AA), adenosine diphosphate (ADP) and TRAP-6. We further investigated procaspase-activating compound 1 (PAC-1) binding and P-selectin membrane expression in platelets stimulated with ADP and TRAP-6. Both DHA and EPA displayed a dose-dependent inhibitory effect on platelet aggregation induced by AA, ADP and TRAP-6. In platelet aggregation induced by AA, DHA significantly improved acetylsalicylic acid (ASA) and triflusal’s inhibitory activity, while EPA enhanced the inhibitory effect of ASA. In combination with EPA, ASA and ticagrelor expressed an increased inhibitory effect towards ADP-induced platelet activation. Both fatty acids could not improve the inhibitory effect of vorapaxar on AA- and ADP-induced platelet aggregation. In the presence of EPA, all antiplatelet drugs displayed a stronger inhibitory effect towards TRAP-6-induced platelet activation. Both omega-3 PUFAs inhibited the membrane expression of α_IIbβ₃, though they had no effect on P-selectin expression induced by ADP or TRAP-6. The antiplatelet drugs exhibited heterogeneity regarding their effect on P-selectin and α_IIbβ₃ membrane expression, while both omega-3 PUFAs inhibited the membrane expression of α_IIbβ₃, though had no effect on P-selectin expression induced by ADP or TRAP-6. The combinatory effect of DHA and EPA with the antiplatelet drugs did not result in enhanced inhibitory activity compared to the sum of the individual effects of each component. Full article

(This article belongs to the Special Issue Platelet Activation in Human Health and Disease)

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24 pages, 2525 KiB

Open AccessArticle

The Effect of a Rotating Magnetic Field on the Regenerative Potential of Platelets

by Elżbieta Cecerska-Heryć, Małgorzata Goszka, Marta Gliźniewicz, Bartłomiej Grygorcewicz, Natalia Serwin, Patrycja Stodolak, Weronika Słodzińska, Radosław Birger, Aleksandra Polikowska, Marta Budkowska, Rafał Rakoczy and Barbara Dołęgowska

Int. J. Mol. Sci. 2024, 25(7), 3644; https://doi.org/10.3390/ijms25073644 - 25 Mar 2024

Cited by 1 | Viewed by 1328

Abstract

Platelets are actively involved in tissue injury site regeneration by producing a wide spectrum of platelet-derived growth factors such as PDGF (platelet-derived growth factor), IGF-1 (insulin-like growth factor), TGF-β1 (transforming growth factor β), FGF (fibroblast growth factor), etc. A rotating magnetic field (RMF) can regulate biological functions, including reduction or induction regarding inflammatory processes, cell differentiation, and gene expression, to determine the effect of an RMF on the regenerative potential of platelets. The study group consisted of 30 healthy female and male volunteers (n = 15), from which plasma was collected. A portion of the plasma was extracted and treated as an internal control group. Subsequent doses of plasma were exposed to RMF at different frequencies (25 and 50 Hz) for 1 and 3 h. Then, the concentrations of growth factors (IGF-1, PDGF-BB, TGF-β1, and FGF-1) were determined in the obtained material by the ELISA method. There were statistically significant differences in the PDGF-BB, TGF-β1, IGF-1, and FGF-1 concentrations between the analyzed groups. The highest concentration of PDGF-BB was observed in the samples placed in RMF for 1 h at 25 Hz. For TGF-β1, the highest concentrations were obtained in the samples exposed to RMF for 3 h at 25 Hz and 1 h at 50 Hz. The highest concentrations of IGF-1 and FGF-1 were shown in plasma placed in RMF for 3 h at 25 Hz. An RMF may increase the regenerative potential of platelets. It was noted that female platelets may respond more strongly to RMF than male platelets. Full article

(This article belongs to the Special Issue Platelet Activation in Human Health and Disease)

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16 pages, 4656 KiB

Open AccessArticle

Platelet-Activating Factor Receptor (PAFR) Regulates Retinal Progenitor/Stem Cells Profile in Ciliary Epithelium Cells

by Barbara Dalmaso, Ildefonso Alves da Silva-Junior, Sonia Jancar and Carolina Beltrame Del Debbio

Int. J. Mol. Sci. 2024, 25(6), 3084; https://doi.org/10.3390/ijms25063084 - 7 Mar 2024

Cited by 1 | Viewed by 1044

Abstract

The retina is a central nervous tissue essential to visual perception and highly susceptible to environmental damage. Lower vertebrate retinas activate intrinsic regeneration mechanisms in response to retinal injury regulated by a specialized population of progenitor cells. The mammalian retina does not have populations of progenitor/stem cells available to activate regeneration, but contains a subpopulation of differentiated cells that can be reprogrammed into retinal stem cells, the ciliary epithelium (CE) cells. Despite the regenerative potential, stem cells derived from CE exhibit limited reprogramming capacity probably associated with the expression of intrinsic regulatory mechanisms. Platelet-activating factor (PAF) is a lipid mediator widely expressed in many cells and plays an important role in stem cell proliferation and differentiation. During mammalian development, PAF receptor signaling showed important effects on retinal progenitors’ cell cycle regulation and neuronal differentiation that need to be further investigated. In this study, our findings suggested a dynamic role for PAF receptor signaling in CE cells, impacting stem cell characteristics and neurosphere formation. We showed that PAF receptors and PAF-related enzymes are downregulated in retinal progenitor/stem cells derived from PE cells. Blocking PAFR activity using antagonists increased the expression of specific progenitor markers, revealing potential implications for retinal tissue development and maintenance. Full article

(This article belongs to the Special Issue Platelet Activation in Human Health and Disease)

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21 pages, 3002 KiB

Open AccessArticle

Study on the Mechanism of the Adrenaline-Evoked Procoagulant Response in Human Platelets

by Agata Gołaszewska, Tomasz Misztal, Adam Kazberuk and Tomasz Rusak

Int. J. Mol. Sci. 2024, 25(5), 2997; https://doi.org/10.3390/ijms25052997 - 5 Mar 2024

Viewed by 1161

Abstract

Adrenaline has recently been found to trigger phosphatidylserine (PS) exposure on blood platelets, resulting in amplification of the coagulation process, but the mechanism is only fragmentarily established. Using a panel of platelet receptors’ antagonists and modulators of signaling pathways, we evaluated the importance of these in adrenaline-evoked PS exposure by flow cytometry. Calcium and sodium ion influx into platelet cytosol, after adrenaline treatment, was examined by fluorimetric measurements. We found a strong reduction in PS exposure after blocking of sodium and calcium ion influx via Na⁺/H⁺ exchanger (NHE) and Na⁺/Ca²⁺ exchanger (NCX), respectively. ADP receptor antagonists produced a moderate inhibitory effect. Substantial limitation of PS exposure was observed in the presence of GPIIb/IIIa antagonist, phosphoinositide-3 kinase (PI3-K) inhibitors, or prostaglandin E₁, a cyclic adenosine monophosphate (cAMP)-elevating agent. We demonstrated that adrenaline may develop a procoagulant response in human platelets with the substantial role of ion exchangers (NHE and NCX), secreted ADP, GPIIb/IIIa-dependent outside-in signaling, and PI3-K. Inhibition of the above mechanisms and increasing cytosolic cAMP seem to be the most efficient procedures to control adrenaline-evoked PS exposure in human platelets. Full article

(This article belongs to the Special Issue Platelet Activation in Human Health and Disease)

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11 pages, 1450 KiB

Open AccessArticle

Impact of Levosimendan and Its Metabolites on Platelet Activation Mechanisms in Patients during Antiplatelet Therapy—Pilot Study

by Joanna Sikora, Krzysztof Pstrągowski, Aleksandra Karczmarska-Wódzka, Patrycja Wszelaki, Katarzyna Buszko and Zbigniew Włodarczyk

Int. J. Mol. Sci. 2024, 25(3), 1824; https://doi.org/10.3390/ijms25031824 - 2 Feb 2024

Viewed by 1139

Abstract

Levosimendan is used for the short-term treatment of severe heart failure or other cardiac conditions. The area of existing clinical applications for levosimendan has increased significantly. This study aimed to assess whether levosimendan and its metabolites impact the mechanisms related to platelet activation. In this study, we included patients with coronary artery disease receiving antiplatelet therapy. We analyzed the pharmacodynamic profile using three independent methods to assess platelet activity. The results of the conducted studies indicate a mechanism of levosimendan that affects the function of platelets, causing higher inhibition of platelet receptors and, thus, their aggregation. It is essential to clarify whether levosimendan may affect platelets due to the need to maintain a balance between bleeding and thrombosis in patients treated with levosimendan. This is especially important in the case of perioperative bleeding. This study was conducted in vitro; the research should be continued and carried out in patients to check the complete pharmacokinetic and pharmacodynamic profile. Full article

(This article belongs to the Special Issue Platelet Activation in Human Health and Disease)

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16 pages, 2054 KiB

Open AccessArticle

Storage of Transfusion Platelet Concentrates Is Associated with Complement Activation and Reduced Ability of Platelets to Respond to Protease-Activated Receptor-1 and Thromboxane A2 Receptor

by Linnea I. Andersson, Dick J. Sjöström, Huy Quang Quach, Kim Hägerström, Lisa Hurler, Erika Kajdácsi, László Cervenak, Zoltán Prohászka, Erik J. M. Toonen, Camilla Mohlin, Tom Eirik Mollnes, Per Sandgren, Ivar Tjernberg and Per H. Nilsson

Int. J. Mol. Sci. 2024, 25(2), 1091; https://doi.org/10.3390/ijms25021091 - 16 Jan 2024

Cited by 2 | Viewed by 1702

Abstract

Platelet activation and the complement system are mutually dependent. Here, we investigated the effects of storage time on complement activation and platelet function in routinely produced platelet concentrates. The platelet concentrates (n = 10) were stored at 22 °C for seven days and assessed daily for complement and platelet activation markers. Additionally, platelet function was analyzed in terms of their responsiveness to protease-activated receptor-1 (PAR-1) and thromboxane A2 receptor (TXA₂R) activation and their capacity to adhere to collagen. Complement activation increased over the storage period for all analyzed markers, including the C1rs/C1-INH complex (fold change (FC) = 1.9; p < 0.001), MASP-1/C1-INH complex (FC = 2.0; p < 0.001), C4c (FC = 1.8, p < 0.001), C3bc (FC = 4.0; p < 0.01), and soluble C5b-9 (FC = 1.7, p < 0.001). Furthermore, the levels of soluble platelet activation markers increased in the concentrates over the seven-day period, including neutrophil-activating peptide-2 (FC = 2.5; p < 0.0001), transforming growth factor beta 1 (FC = 1.9; p < 0.001) and platelet factor 4 (FC = 2.1; p < 0.0001). The ability of platelets to respond to activation, as measured by surface expression of CD62P and CD63, decreased by 19% and 24% (p < 0.05) for PAR-1 and 69–72% (p < 0.05) for TXA₂R activation, respectively, on Day 7 compared to Day 1. The extent of platelet binding to collagen was not significantly impaired during storage. In conclusion, we demonstrated that complement activation increased during the storage of platelets, and this correlated with increased platelet activation and a reduced ability of the platelets to respond to, primarily, TXA₂R activation. Full article

(This article belongs to the Special Issue Platelet Activation in Human Health and Disease)

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Review

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20 pages, 1481 KiB

Open AccessReview

The Ways of the Virus: Interactions of Platelets and Red Blood Cells with SARS-CoV-2, and Their Potential Pathophysiological Significance in COVID-19

by Mikhail A. Panteleev, Anastasia N. Sveshnikova, Soslan S. Shakhidzhanov, Alexey V. Zamaraev, Fazoil I. Ataullakhanov and Aleksandr G. Rumyantsev

Int. J. Mol. Sci. 2023, 24(24), 17291; https://doi.org/10.3390/ijms242417291 - 9 Dec 2023

Viewed by 2545

Abstract

The hematological effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important in COVID-19 pathophysiology. However, the interactions of SARS-CoV-2 with platelets and red blood cells are still poorly understood. There are conflicting data regarding the mechanisms and significance of these interactions. The aim of this review is to put together available data and discuss hypotheses, the known and suspected effects of the virus on these blood cells, their pathophysiological and diagnostic significance, and the potential role of platelets and red blood cells in the virus’s transport, propagation, and clearance by the immune system. We pay particular attention to the mutual activation of platelets, the immune system, the endothelium, and blood coagulation and how this changes with the evolution of SARS-CoV-2. There is now convincing evidence that platelets, along with platelet and erythroid precursors (but not mature erythrocytes), are frequently infected by SARS-CoV-2 and functionally changed. The mechanisms of infection of these cells and their role are not yet entirely clear. Still, the changes in platelets and red blood cells in COVID-19 are significantly associated with disease severity and are likely to have prognostic and pathophysiological significance in the development of thrombotic and pulmonary complications. Full article

(This article belongs to the Special Issue Platelet Activation in Human Health and Disease)

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