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14 pages, 2492 KiB

Open AccessArticle

Variations in Blood Platelet Proteome and Transcriptome Revealed Altered Expression of Transgelin-2 in Acute Coronary Syndrome Patients

by Rafał Szelenberger, Paweł Jóźwiak, Michał Kacprzak, Michał Bijak, Marzenna Zielińska, Alina Olender and Joanna Saluk-Bijak

Int. J. Mol. Sci. 2022, 23(11), 6340; https://doi.org/10.3390/ijms23116340 - 06 Jun 2022

Viewed by 2017

Abstract

Proteomic analyses based on mass spectrometry provide a powerful tool for the simultaneous identification of proteins and their signatures. Disorders detection at the molecular level delivers an immense impact for a better understanding of the pathogenesis and etiology of various diseases. Acute coronary [...] Read more.

Proteomic analyses based on mass spectrometry provide a powerful tool for the simultaneous identification of proteins and their signatures. Disorders detection at the molecular level delivers an immense impact for a better understanding of the pathogenesis and etiology of various diseases. Acute coronary syndrome (ACS) refers to a group of heart diseases generally associated with rupture of an atherosclerotic plaque and partial or complete thrombotic obstruction of the blood flow in the infarct-related coronary artery. The essential role in the pathogenesis of ACS is related to the abnormal, pathological activation of blood platelets. The multifactorial and complex character of ACS indicates the need to explain the molecular mechanisms responsible for thrombosis. In our study, we performed screening and comparative analysis of platelet proteome from ACS patients and healthy donors. Two-dimensional fluorescence difference gel electrophoresis and nanoscale liquid chromatography coupled to tandem mass spectrometry showed altered expressions of six proteins (i.e., vinculin, transgelin-2, fibrinogen β and γ chains, apolipoprotein a1, and tubulin β), with the overlapping increased expression at the mRNA level for transgelin-2. Dysregulation in protein expression identified in our study may be associated with an increased risk of thrombotic events, correlated with a higher aggregability of blood platelets and induced shape change, thus explaining the phenomenon of the hyperreactivity of blood platelets in ACS. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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10 pages, 1150 KiB

Open AccessArticle

Spontaneous Platelet Aggregation in Blood Is Mediated by FcγRIIA Stimulation of Bruton’s Tyrosine Kinase

by Rundan Duan, Luise Goldmann, Ya Li, Christian Weber, Wolfgang Siess and Philipp von Hundelshausen

Int. J. Mol. Sci. 2022, 23(1), 76; https://doi.org/10.3390/ijms23010076 - 22 Dec 2021

Cited by 3 | Viewed by 1918

Abstract

High platelet reactivity leading to spontaneous platelet aggregation (SPA) is a hallmark of cardiovascular diseases; however, the mechanism underlying SPA remains obscure. Platelet aggregation in stirred hirudin-anticoagulated blood was measured by multiple electrode aggregometry (MEA) for 10 min. SPA started after a delay [...] Read more.

High platelet reactivity leading to spontaneous platelet aggregation (SPA) is a hallmark of cardiovascular diseases; however, the mechanism underlying SPA remains obscure. Platelet aggregation in stirred hirudin-anticoagulated blood was measured by multiple electrode aggregometry (MEA) for 10 min. SPA started after a delay of 2–3 min. In our cohort of healthy blood donors (n = 118), nine donors (8%) with high SPA (>250 AU*min) were detected. Pre-incubation of blood with two different antibodies against the platelet Fc-receptor (anti-FcγRIIA, CD32a) significantly reduced high SPA by 86%. High but not normal SPA was dose-dependently and significantly reduced by blocking Fc of human IgG with a specific antibody. SPA was completely abrogated by blood pre-incubation with the reversible Btk-inhibitor (BTKi) fenebrutinib (50 nM), and 3 h after intake of the irreversible BTKi ibrutinib (280 mg) by healthy volunteers. Increased SPA was associated with higher platelet GPVI reactivity. Anti-platelet factor 4 (PF4)/polyanion IgG complexes were excluded as activators of the platelet Fc-receptor. Our results indicate that high SPA in blood is due to platelet FcγRIIA stimulation by unidentified IgG complexes and mediated by Btk activation. The relevance of our findings for SPA as possible risk factor of cardiovascular diseases and pathogenic factor contributing to certain autoimmune diseases is discussed. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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17 pages, 2059 KiB

Open AccessArticle

Acetyl-CoA Carboxylase Inhibitor CP640.186 Increases Tubulin Acetylation and Impairs Thrombin-Induced Platelet Aggregation

by Marie Octave, Laurence Pirotton, Audrey Ginion, Valentine Robaux, Sophie Lepropre, Jérôme Ambroise, Caroline Bouzin, Bruno Guigas, Martin Giera, Marc Foretz, Luc Bertrand, Christophe Beauloye and Sandrine Horman

Int. J. Mol. Sci. 2021, 22(23), 13129; https://doi.org/10.3390/ijms222313129 - 04 Dec 2021

Cited by 4 | Viewed by 1951

Abstract

Acetyl-CoA carboxylase (ACC) is the first enzyme regulating de novo lipid synthesis via the carboxylation of acetyl-CoA into malonyl-CoA. The inhibition of its activity decreases lipogenesis and, in parallel, increases the acetyl-CoA content, which serves as a substrate for protein acetylation. Several findings [...] Read more.

Acetyl-CoA carboxylase (ACC) is the first enzyme regulating de novo lipid synthesis via the carboxylation of acetyl-CoA into malonyl-CoA. The inhibition of its activity decreases lipogenesis and, in parallel, increases the acetyl-CoA content, which serves as a substrate for protein acetylation. Several findings support a role for acetylation signaling in coordinating signaling systems that drive platelet cytoskeletal changes and aggregation. Therefore, we investigated the impact of ACC inhibition on tubulin acetylation and platelet functions. Human platelets were incubated 2 h with CP640.186, a pharmacological ACC inhibitor, prior to thrombin stimulation. We have herein demonstrated that CP640.186 treatment does not affect overall platelet lipid content, yet it is associated with increased tubulin acetylation levels, both at the basal state and after thrombin stimulation. This resulted in impaired platelet aggregation. Similar results were obtained using human platelets that were pretreated with tubacin, an inhibitor of tubulin deacetylase HDAC6. In addition, both ACC and HDAC6 inhibitions block key platelet cytoskeleton signaling events, including Rac1 GTPase activation and the phosphorylation of its downstream effector, p21-activated kinase 2 (PAK2). However, neither CP640.186 nor tubacin affects thrombin-induced actin cytoskeleton remodeling, while ACC inhibition results in decreased thrombin-induced reactive oxygen species (ROS) production and extracellular signal-regulated kinase (ERK) phosphorylation. We conclude that when using washed human platelets, ACC inhibition limits tubulin deacetylation upon thrombin stimulation, which in turn impairs platelet aggregation. The mechanism involves a downregulation of the Rac1/PAK2 pathway, being independent of actin cytoskeleton. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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16 pages, 10770 KiB

Open AccessArticle

Ultrastructural Study of Platelet Behavior and Interrelationship in Sprouting and Intussusceptive Angiogenesis during Arterial Intimal Thickening Formation

by Lucio Díaz-Flores, Ricardo Gutiérrez, Maria Pino García, Miriam González-Gómez, Lucio Díaz-Flores, Jr., Sara Gayoso, Jose Luis Carrasco and Hugo Álvarez-Argüelles

Int. J. Mol. Sci. 2021, 22(23), 13001; https://doi.org/10.3390/ijms222313001 - 30 Nov 2021

Cited by 3 | Viewed by 1565

Abstract

Platelets in atherosclerosis, bypass stenosis, and restenosis have been extensively assessed. However, a sequential ultrastructural study of platelets in angiogenesis during the early phases of these lesions has received less attention. Our objective was the study of platelets in angiogenesis and vessel regression [...] Read more.

Platelets in atherosclerosis, bypass stenosis, and restenosis have been extensively assessed. However, a sequential ultrastructural study of platelets in angiogenesis during the early phases of these lesions has received less attention. Our objective was the study of platelets in angiogenesis and vessel regression during intimal thickening (IT) formation, a precursor process of these occlusive vascular diseases. For this purpose, we used an experimental model of rat occluded arteries and procedures for ultrastructural observation. The results show (a) the absence of platelet adhesion in the de-endothelialized occluded arterial segment isolated from the circulation, (b) that intraarterial myriad platelets contributed from neovessels originated by sprouting angiogenesis from the periarterial microvasculature, (c) the association of platelets with blood components (fibrin, neutrophils, macrophages, and eosinophils) and non-polarized endothelial cells (ECs) forming aggregates (spheroids) in the arterial lumen, (d) the establishment of peg-and-socket junctions between platelets and polarized Ecs during intussusceptive angiogenesis originated from the EC aggregates, with the initial formation of IT, and (e) the aggregation of platelets in regressing neovessels (‘transitory paracrine organoid’) and IT increases. In conclusion, in sprouting and intussusceptive angiogenesis and vessel regression during IT formation, we contribute sequential ultrastructural findings on platelet behavior and relationships, which can be the basis for further studies using other procedures. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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19 pages, 4414 KiB

Open AccessArticle

Impact of Amyloid-β on Platelet Mitochondrial Function and Platelet–Mediated Amyloid Aggregation in Alzheimer’s Disease

by Lili Donner, Tobias Feige, Carolin Freiburg, Laura Mara Toska, Andreas S. Reichert, Madhumita Chatterjee and Margitta Elvers

Int. J. Mol. Sci. 2021, 22(17), 9633; https://doi.org/10.3390/ijms22179633 - 06 Sep 2021

Cited by 14 | Viewed by 2771

Abstract

Background: Alzheimer’s disease (AD) is characterized by an accumulation of amyloid β (Aβ) peptides in the brain and mitochondrial dysfunction. Platelet activation is enhanced in AD and platelets contribute to AD pathology by their ability to facilitate soluble Aβ to form Aβ aggregates. [...] Read more.

Background: Alzheimer’s disease (AD) is characterized by an accumulation of amyloid β (Aβ) peptides in the brain and mitochondrial dysfunction. Platelet activation is enhanced in AD and platelets contribute to AD pathology by their ability to facilitate soluble Aβ to form Aβ aggregates. Thus, anti-platelet therapy reduces the formation of cerebral amyloid angiopathy in AD transgenic mice. Platelet mitochondrial dysfunction plays a regulatory role in thrombotic response, but its significance in AD is unknown and explored herein. Methods: The effects of Aβ-mediated mitochondrial dysfunction in platelets were investigated in vitro. Results: Aβ40 stimulation of human platelets led to elevated reactive oxygen species (ROS) and superoxide production, while reduced mitochondrial membrane potential and oxygen consumption rate. Enhanced mitochondrial dysfunction triggered platelet-mediated Aβ40 aggregate formation through GPVI-mediated ROS production, leading to enhanced integrin αII_bβ₃ activation during synergistic stimulation from ADP and Aβ40. Aβ40 aggregate formation of human and murine (APP23) platelets were comparable to controls and could be reduced by the antioxidant vitamin C. Conclusions: Mitochondrial dysfunction contributes to platelet-mediated Aβ aggregate formation and might be a promising target to limit platelet activation exaggerated pathological manifestations in AD. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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12 pages, 2910 KiB

Open AccessArticle

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways

by Vittoria Cammisotto, Francesco Baratta, Valentina Castellani, Simona Bartimoccia, Cristina Nocella, Laura D’Erasmo, Nicholas Cocomello, Cristina Barale, Roberto Scicali, Antonino Di Pino, Salvatore Piro, Maria Del Ben, Marcello Arca, Isabella Russo, Francesco Purrello, Roberto Carnevale, Francesco Violi, Daniele Pastori and Pasquale Pignatelli

Int. J. Mol. Sci. 2021, 22(13), 7193; https://doi.org/10.3390/ijms22137193 - 03 Jul 2021

Cited by 27 | Viewed by 2765

Abstract

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a [...] Read more.

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before–after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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12 pages, 1671 KiB

Open AccessArticle

Thrombopoietin Contributes to Enhanced Platelet Activation in Patients with Type 1 Diabetes Mellitus

by Ornella Bosco, Barbara Vizio, Gabriella Gruden, Martina Schiavello, Bartolomeo Lorenzati, Paolo Cavallo-Perin, Isabella Russo, Giuseppe Montrucchio and Enrico Lupia

Int. J. Mol. Sci. 2021, 22(13), 7032; https://doi.org/10.3390/ijms22137032 - 29 Jun 2021

Cited by 4 | Viewed by 2146

Abstract

Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM). Enhanced platelet reactivity is considered a main determinant of the increased atherothrombotic risk of diabetic patients. Thrombopoietin (THPO), a humoral growth factor able to [...] Read more.

Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM). Enhanced platelet reactivity is considered a main determinant of the increased atherothrombotic risk of diabetic patients. Thrombopoietin (THPO), a humoral growth factor able to stimulate megakaryocyte proliferation and differentiation, also modulates the response of mature platelets by enhancing both activation and binding to leukocytes in response to different agonists. Increased THPO levels have been reported in different clinical conditions characterized by a generalized pro-thrombotic state, from acute coronary syndromes to sepsis/septic shock, and associated with elevated indices of platelet activation. To investigate the potential contribution of elevated THPO levels in platelet activation in T1DM patients, we studied 28 T1DM patients and 28 healthy subjects. We measured plasma levels of THPO, as well as platelet-leukocyte binding, P-selectin, and THPO receptor (THPOR) platelet expression. The priming activity of plasma from diabetic patients or healthy subjects on platelet–leukocyte binding and the role of THPO on this effect was also studied in vitro. T1DM patients had higher circulating THPO levels and increased platelet–monocyte and platelet–granulocyte binding, as well as platelet P-selectin expression, compared to healthy subjects, whereas platelet expression of THPOR did not differ between the two groups. THPO concentrations correlated with platelet–leukocyte binding, as well as with fasting glucose and Hb1Ac. In vitro, plasma from diabetic patients, but not from healthy subjects, primed platelet–leukocyte binding and platelet P-selectin expression. Blocking THPO biological activity using a specific inhibitor prevented the priming effect induced by plasma from diabetic patients. In conclusion, augmented THPO may enhance platelet activation in patients with T1DM, potentially participating in increasing atherosclerotic risk. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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16 pages, 2302 KiB

Open AccessArticle

Curcumin at Low Doses Potentiates and at High Doses Inhibits ABT-737-Induced Platelet Apoptosis

by Natalia Rukoyatkina, Valentina Shpakova, Julia Sudnitsyna, Michael Panteleev, Stephanie Makhoul, Stepan Gambaryan and Kerstin Jurk

Int. J. Mol. Sci. 2021, 22(10), 5405; https://doi.org/10.3390/ijms22105405 - 20 May 2021

Cited by 6 | Viewed by 2994

Abstract

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is [...] Read more.

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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15 pages, 2357 KiB

Open AccessArticle

Adenosine Receptor Agonist HE-NECA Enhances Antithrombotic Activities of Cangrelor and Prasugrel in vivo by Decreasing of Fibrinogen Density in Thrombus

by Dawid Polak, Marcin Talar, Nina Wolska, Dagmara W. Wojkowska, Kamil Karolczak, Karol Kramkowski, Tomasz A. Bonda, Cezary Watala and Tomasz Przygodzki

Int. J. Mol. Sci. 2021, 22(6), 3074; https://doi.org/10.3390/ijms22063074 - 17 Mar 2021

Cited by 4 | Viewed by 2100

Abstract

Blood platelets’ adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo [...] Read more.

Blood platelets’ adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo evidence for the antithrombotic activity of AR agonists published to date were limited, however, to the usage of relatively high doses given in bolus. The present study was aimed at verifying if these substances used in lower doses in combination with inhibitors of P2Y₁₂ could serve as components of dual anti-platelet therapy. We have found that a selective A_2A agonist 2-hexynyl-5’-N-ethylcarboxamidoadenosine (HE-NECA) improved the anti-thrombotic properties of either cangrelor or prasugrel in the model of ferric chloride-induced experimental thrombosis in mice. Importantly, HE-NECA was effective not only when applied in bolus as other AR agonists in the up-to-date published studies, but also when given chronically. In vitro thrombus formation under flow conditions revealed that HE-NECA enhanced the ability of P2Y₁₂ inhibitors to decrease fibrinogen content in thrombi, possibly resulting in their lower stability. Adenosine receptor agonists possess a certain hypotensive effect and an ability to increase the blood–brain barrier permeability. Therefore, the effects of anti-thrombotic doses of HE-NECA on blood pressure and the blood–brain barrier permeability in mice were tested. HE-NECA applied in bolus caused a significant hypotension in mice, but the effect was much lower when the substance was given in doses corresponding to that obtained by chronic administration. At the same time, no significant effect of HE-NECA was observed on the blood–brain barrier. We conclude that chronic administration of the A_2A agonist can be considered a potential component of a dual antithrombotic therapy. However, due to the hypotensive effect of the substances, dosage and administration must be elaborated to minimize the side-effects. The total number of animals used in the experiments was 146. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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Review

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13 pages, 747 KiB

Open AccessReview

Platelets Contribution to Thrombin Generation in Philadelphia-Negative Myeloproliferative Neoplasms: The “Circulating Wound” Model

by Alessandro Lucchesi, Roberta Napolitano, Maria Teresa Bochicchio, Giulio Giordano and Mariasanta Napolitano

Int. J. Mol. Sci. 2021, 22(21), 11343; https://doi.org/10.3390/ijms222111343 - 20 Oct 2021

Cited by 5 | Viewed by 2420

Abstract

Current cytoreductive and antithrombotic strategies in MPNs are mostly based on cell counts and on patient’s demographic and clinical history. Despite the numerous studies conducted on platelet function and on the role of plasma factors, an accurate and reliable method to dynamically quantify [...] Read more.

Current cytoreductive and antithrombotic strategies in MPNs are mostly based on cell counts and on patient’s demographic and clinical history. Despite the numerous studies conducted on platelet function and on the role of plasma factors, an accurate and reliable method to dynamically quantify the hypercoagulability states of these conditions is not yet part of clinical practice. Starting from our experience, and after having sifted through the literature, we propose an in-depth narrative report on the contribution of the clonal platelets of MPNs—rich in tissue factor (TF)—in promoting a perpetual procoagulant mechanism. The whole process results in an unbalanced generation of thrombin and is self-maintained by Protease Activated Receptors (PARs). We chose to define this model as a “circulating wound”, as it indisputably links the coagulation, inflammation, and fibrotic progression of the disease, in analogy with what happens in some solid tumours. The platelet contribution to thrombin generation results in triggering a vicious circle supported by the PARs/TGF-beta axis. PAR antagonists could therefore be a good option for target therapy, both to contain the risk of vascular events and to slow the progression of the disease towards end-stage forms. Both the new and old strategies, however, will require tools capable of measuring procoagulant or prohaemorrhagic states in a more extensive and dynamic way to favour a less empirical management of MPNs and their potential clinical complications. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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18 pages, 1620 KiB

Open AccessReview

Changes in Maternal Platelet Physiology during Gestation and Their Interaction with Trophoblasts

by Désirée Forstner, Jacqueline Guettler and Martin Gauster

Int. J. Mol. Sci. 2021, 22(19), 10732; https://doi.org/10.3390/ijms221910732 - 03 Oct 2021

Cited by 15 | Viewed by 3120

Abstract

Upon activation, maternal platelets provide a source of proinflammatory mediators in the intervillous space of the placenta. Therefore, platelet-derived factors may interfere with different trophoblast subtypes of the developing human placenta and might cause altered hormone secretion and placental dysfunction later on in [...] Read more.

Upon activation, maternal platelets provide a source of proinflammatory mediators in the intervillous space of the placenta. Therefore, platelet-derived factors may interfere with different trophoblast subtypes of the developing human placenta and might cause altered hormone secretion and placental dysfunction later on in pregnancy. Increased platelet activation, and the subsequent occurrence of placental fibrinoid deposition, are linked to placenta pathologies such as preeclampsia. The composition and release of platelet-derived factors change over gestation and provide a potential source of predicting biomarkers for the developing fetus and the mother. This review indicates possible mechanisms of platelet-trophoblast interactions and discusses the effect of increased platelet activation on placenta development. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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14 pages, 1908 KiB

Open AccessReview

Vitamin D and Platelets: A Menacing Duo in COVID-19 and Potential Relation to Bone Remodeling

by Francesca Salamanna, Melania Maglio, Maria Sartori, Maria Paola Landini and Milena Fini

Int. J. Mol. Sci. 2021, 22(18), 10010; https://doi.org/10.3390/ijms221810010 - 16 Sep 2021

Cited by 12 | Viewed by 7237

Abstract

Global data correlate severe vitamin D deficiency with COVID-19-associated coagulopathy, further suggesting the presence of a hypercoagulable state in severe COVID-19 patients, which could promote thrombosis in the lungs and in other organs. The feedback loop between COVID-19-associated coagulopathy and vitamin D also [...] Read more.

Global data correlate severe vitamin D deficiency with COVID-19-associated coagulopathy, further suggesting the presence of a hypercoagulable state in severe COVID-19 patients, which could promote thrombosis in the lungs and in other organs. The feedback loop between COVID-19-associated coagulopathy and vitamin D also involves platelets (PLTs), since vitamin D deficiency stimulates PLT activation and aggregation and increases fibrinolysis and thrombosis. Vitamin D and PLTs share and play specific roles not only in coagulation and thrombosis but also during inflammation, endothelial dysfunction, and immune response. Additionally, another ‘fil rouge’ between vitamin D and PLTs is represented by their role in mineral metabolism and bone health, since vitamin D deficiency, low PLT count, and altered PLT-related parameters are linked to abnormal bone remodeling in certain pathological conditions, such as osteoporosis (OP). Hence, it is possible to speculate that severe COVID-19 patients are characterized by the presence of several predisposing factors to bone fragility and OP that may be monitored to avoid potential complications. Here, we hypothesize different pervasive actions of vitamin D and PLT association in COVID-19, also allowing for potential preliminary information on bone health status during COVID-19 infection. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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20 pages, 1060 KiB

Open AccessReview

Megakaryopoiesis and Platelet Biology: Roles of Transcription Factors and Emerging Clinical Implications

by Ji-Yoon Noh

Int. J. Mol. Sci. 2021, 22(17), 9615; https://doi.org/10.3390/ijms22179615 - 05 Sep 2021

Cited by 16 | Viewed by 5814

Abstract

Platelets play a critical role in hemostasis and thrombus formation. Platelets are small, anucleate, and short-lived blood cells that are produced by the large, polyploid, and hematopoietic stem cell (HSC)-derived megakaryocytes in bone marrow. Approximately 3000 platelets are released from one megakaryocyte, and [...] Read more.

Platelets play a critical role in hemostasis and thrombus formation. Platelets are small, anucleate, and short-lived blood cells that are produced by the large, polyploid, and hematopoietic stem cell (HSC)-derived megakaryocytes in bone marrow. Approximately 3000 platelets are released from one megakaryocyte, and thus, it is important to understand the physiologically relevant mechanism of development of mature megakaryocytes. Many genes, including several key transcription factors, have been shown to be crucial for platelet biogenesis. Mutations in these genes can perturb megakaryopoiesis or thrombopoiesis, resulting in thrombocytopenia. Metabolic changes owing to inflammation, ageing, or diseases such as cancer, in which platelets play crucial roles in disease development, can also affect platelet biogenesis. In this review, I describe the characteristics of platelets and megakaryocytes in terms of their differentiation processes. The role of several critical transcription factors have been discussed to better understand the changes in platelet biogenesis that occur during disease or ageing. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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15 pages, 304 KiB

Open AccessReview

Blood Platelets as an Important but Underrated Circulating Source of TGFβ

by Kamil Karolczak and Cezary Watala

Int. J. Mol. Sci. 2021, 22(9), 4492; https://doi.org/10.3390/ijms22094492 - 26 Apr 2021

Cited by 36 | Viewed by 3590

Abstract

When treating diseases related primarily to tissue remodeling and fibrosis, it is desirable to regulate TGFβ concentration and modulate its biological effects. The highest cellular concentrations of TGFβ are found in platelets, with about 40% of all TGFβ found in peripheral blood plasma [...] Read more.

When treating diseases related primarily to tissue remodeling and fibrosis, it is desirable to regulate TGFβ concentration and modulate its biological effects. The highest cellular concentrations of TGFβ are found in platelets, with about 40% of all TGFβ found in peripheral blood plasma being secreted by them. Therefore, an understanding of the mechanisms of TGFβ secretion from platelets may be of key importance for medicine. Unfortunately, despite the finding that platelets are an important regulator of TGFβ levels, little research has been carried out into the development of platelet-directed therapies that might modulate the TGFβ-dependent processes. Nevertheless, there are some very encouraging reports suggesting that platelet TGFβ may be specifically involved in cardiovascular diseases, liver fibrosis, tumour metastasis, cerebral malaria and in the regulation of inflammatory cell functions. The purpose of this review is to briefly summarize these few, extremely encouraging reports to indicate the state of current knowledge in this topic. It also attempts to better characterize the influence of TGFβ on platelet activation and reactivity, and its shaping of the roles of blood platelets in haemostasis and thrombosis. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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17 pages, 991 KiB

Open AccessReview

The Role of the Proteasome in Platelet Function

by Abed El-Hakim El-Kadiry and Yahye Merhi

Int. J. Mol. Sci. 2021, 22(8), 3999; https://doi.org/10.3390/ijms22083999 - 13 Apr 2021

Cited by 11 | Viewed by 2860

Abstract

Platelets are megakaryocyte-derived acellular fragments prepped to maintain primary hemostasis and thrombosis by preserving vascular integrity. Although they lack nuclei, platelets harbor functional genomic mediators that bolster platelet activity in a signal-specific manner by performing limited de novo protein synthesis. Furthermore, despite their [...] Read more.

Platelets are megakaryocyte-derived acellular fragments prepped to maintain primary hemostasis and thrombosis by preserving vascular integrity. Although they lack nuclei, platelets harbor functional genomic mediators that bolster platelet activity in a signal-specific manner by performing limited de novo protein synthesis. Furthermore, despite their limited protein synthesis, platelets are equipped with multiple protein degradation mechanisms, such as the proteasome. In nucleated cells, the functions of the proteasome are well established and primarily include proteostasis among a myriad of other signaling processes. However, the role of proteasome-mediated protein degradation in platelets remains elusive. In this review article, we recapitulate the developing literature on the functions of the proteasome in platelets, discussing its emerging regulatory role in platelet viability and function and highlighting how its functional coupling with the transcription factor NF-κB constitutes a novel potential therapeutic target in atherothrombotic diseases. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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