Research

17 pages, 3560 KiB

Open AccessArticle

Platelet-Derived Extracellular Vesicles as Lipid Carriers in Severe Allergic Inflammation

by Alba Couto-Rodriguez, Alma Villaseñor, Carmela Pablo-Torres, David Obeso, María Fernanda Rey-Stolle, Héctor Peinado, José Luis Bueno, Mar Reaño-Martos, Alfredo Iglesias Cadarso, Cristina Gomez-Casado, Coral Barbas, Domingo Barber, María M. Escribese and Elena Izquierdo

Int. J. Mol. Sci. 2023, 24(16), 12714; https://doi.org/10.3390/ijms241612714 - 12 Aug 2023

Viewed by 1247

Abstract

The resolution of inflammation is a complex process that is critical for removing inflammatory cells and restoring tissue function. The dysregulation of these mechanisms leads to chronic inflammatory disorders. Platelets, essential cells for preserving homeostasis, are thought to play a role in inflammation [...] Read more.

The resolution of inflammation is a complex process that is critical for removing inflammatory cells and restoring tissue function. The dysregulation of these mechanisms leads to chronic inflammatory disorders. Platelets, essential cells for preserving homeostasis, are thought to play a role in inflammation as they are a source of immunomodulatory factors. Our aim was to identify key metabolites carried by platelet-derived extracellular vesicles (PL-EVs) in a model of allergic inflammation. PL-EVs were isolated by serial ultracentrifugation using platelet-rich plasma samples obtained from platelet apheresis from severely (n = 6) and mildly (n = 6) allergic patients and non-allergic individuals used as controls (n = 8). PL-EVs were analysed by a multiplatform approach using liquid and gas chromatography coupled to mass spectrometry (LC-MS and GC-MS, respectively). PL-EVs obtained from severely and mildly allergic patients and control individuals presented comparable particle concentrations and sizes with similar protein concentrations. Strikingly, PL-EVs differed in their lipid and metabolic content according to the severity of inflammation. L-carnitine, ceramide (Cer (d18:0/24:0)), and several triglycerides, all of which seem to be involved in apoptosis and regulatory T functions, were higher in PL-EVs from patients with mild allergic inflammation than in those with severe inflammation. In contrast, PL-EVs obtained from patients with severe allergic inflammation showed an alteration in the arachidonic acid pathway. This study demonstrates that PL-EVs carry specific lipids and metabolites according to the degree of inflammation in allergic patients and propose novel perspectives for characterising the progression of allergic inflammation. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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15 pages, 2109 KiB

Open AccessArticle

Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac

by Yukiko Enomoto, Takashi Onuma, Takamitsu Hori, Kumiko Tanabe, Kyohei Ueda, Daisuke Mizutani, Tomoaki Doi, Rie Matsushima-Nishiwaki, Shinji Ogura, Hiroki Iida, Toru Iwama, Osamu Kozawa and Haruhiko Tokuda

Int. J. Mol. Sci. 2023, 24(11), 9716; https://doi.org/10.3390/ijms24119716 - 03 Jun 2023

Viewed by 1046

Abstract

CXCL12, belonging to the CXC chemokine family, is a weak agonist of platelet aggregation. We previously reported that the combination of CXCL12 and collagen at low doses synergistically activates platelets via not CXCR7 but CXCR4, a specific receptor for CXCL12 on the plasma [...] Read more.

CXCL12, belonging to the CXC chemokine family, is a weak agonist of platelet aggregation. We previously reported that the combination of CXCL12 and collagen at low doses synergistically activates platelets via not CXCR7 but CXCR4, a specific receptor for CXCL12 on the plasma membrane. Recently, we reported that not Rho/Rho kinase, but Rac is involved in the platelet aggregation induced by this combination. Ristocetin is an activator of the von Willebrand factor that interacts with glycoprotein (GP) Ib/IX/V, which generates thromboxane A2 via phospholipase A2 activation, resulting in the release of the soluble CD40 ligand (sCD40L) from human platelets. In the present study, we investigated the effects of a combination of ristocetin and CXCL12 at low doses on human platelet activation and its underlying mechanisms. Simultaneous stimulation with ristocetin and CXCL12 at subthreshold doses synergistically induce platelet aggregation. A monoclonal antibody against not CXCR7 but CXCR4 suppressed platelet aggregation induced by the combination of ristocetin and CXCL12 at low doses. This combination induces a transient increase in the levels of both GTP-binding Rho and Rac, followed by an increase in phosphorylated cofilin. The ristocetin and CXCL12-induced platelet aggregation as well as the sCD40L release were remarkably enhanced by Y27362, an inhibitor of Rho-kinase, but reduced by NSC23766, an inhibitor of the Rac-guanine nucleotide exchange factor interaction. These results strongly suggest that the combination of ristocetin and CXCL12 at low doses synergistically induces human platelet activation via Rac and that this activation is negatively regulated by the simultaneous activation of Rho/Rho-kinase. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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11 pages, 1762 KiB

Open AccessArticle

Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm

by Armin Muminovic, Yuliy Y. Chirkov and John D. Horowitz

Int. J. Mol. Sci. 2023, 24(11), 9273; https://doi.org/10.3390/ijms24119273 - 25 May 2023

Viewed by 975

Abstract

Impairment of the nitric oxide/soluble guanylate cyclase (NO)/sGC) signalling cascade is associated with many forms of cardiovascular disease, resulting not only in compromised vasodilatation but also loss of anti-aggregatory homeostasis. Myocardial ischaemia, heart failure, and atrial fibrillation are associated with moderate impairment of [...] Read more.

Impairment of the nitric oxide/soluble guanylate cyclase (NO)/sGC) signalling cascade is associated with many forms of cardiovascular disease, resulting not only in compromised vasodilatation but also loss of anti-aggregatory homeostasis. Myocardial ischaemia, heart failure, and atrial fibrillation are associated with moderate impairment of NO/sGC signalling, and we have recently demonstrated that coronary artery spasm (CAS) is engendered by severe impairment of platelet NO/sGC activity resulting in combined platelet and vascular endothelial damage. We therefore sought to determine whether sGC stimulators or activators might normalise NO/sGC homeostasis in platelets. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP), the sGC stimulator riociguat (RIO), and the sCG activator cinaciguat (CINA) alone or in addition to SNP were quantitated. Three groups of individuals were compared: normal subjects (n = 9), patients (Group 1) with myocardial ischaemia, heart failure and/or atrial fibrillation (n = 30), and patients (Group 2) in the chronic stage of CAS (n = 16). As expected, responses to SNP were impaired (p = 0.02) in patients versus normal subjects, with Group 2 patients most severely affected (p = 0.005). RIO alone exerted no anti-aggregatory effects but potentiated responses to SNP to a similar extent irrespective of baseline SNP response. CINA exerted only intrinsic anti-aggregatory effects, but the extent of these varied directly (r = 0.54; p = 0.0009) with individual responses to SNP. Thus, both RIO and CINA tend to normalise anti-aggregatory function in patients in whom NO/sGC signalling is impaired. The anti-aggregatory effects of RIO consist entirely of potentiation of NO, which is not selective of platelet NO resistance. However, the intrinsic anti-aggregatory effects of CINA are most marked in individuals with initially normal NO/sGC signalling, and thus their magnitude is at variance with extent of physiological impairment. These data suggest that RIO and other sGC stimulators should be evaluated for clinical utility in both prophylaxis and treatment of CAS. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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23 pages, 5273 KiB

Open AccessArticle

Gene Expression Behavior of a Set of Genes in Platelet and Tissue Samples from Patients with Breast Cancer

by Luis A. Burciaga-Hernandez, Cecilia F. Cueto-Villalobos, Nancy Ortega-Piñon, Irma E. Gonzalez-Curiel, Susana Godina-Gonzalez, Gwendolyne Mendez-Frausto, Anna P. Aguilar-Esquivel, Vilma Maldonado-Lagunas, Luis E. Guerrero-de la Torre, Jorge Melendez-Zajgla, Erika K. Sanchez-Garcia, Irma B. Mitre-Aguilar and Gretel Mendoza-Almanza

Int. J. Mol. Sci. 2023, 24(9), 8348; https://doi.org/10.3390/ijms24098348 - 06 May 2023

Cited by 1 | Viewed by 1748

Abstract

The tumor microenvironment (TME) is constituted by a great diversity of highly dynamic cell populations, each of which contributes ligands, receptors, soluble proteins, mRNAs, and miRNAs, in order to regulate cellular activities within the TME and even promote processes such as angiogenesis or [...] Read more.

The tumor microenvironment (TME) is constituted by a great diversity of highly dynamic cell populations, each of which contributes ligands, receptors, soluble proteins, mRNAs, and miRNAs, in order to regulate cellular activities within the TME and even promote processes such as angiogenesis or metastasis. Intravasated platelets (PLT) undergo changes in the TME that convert them into tumor-educated platelets (TEP), which supports the development of cancer, angiogenesis, and metastasis through the degranulation and release of biomolecules. Several authors have reported that the deregulation of PF4, VEGF, PDGF, ANG-1, WASF3, LAPTM4B, TPM3, and TAC1 genes participates in breast cancer progression, angiogenesis, and metastasis. The present work aimed to analyze the expression levels of this set of genes in tumor tissues and platelets derived from breast cancer patients by reverse transcription-quantitative polymerase chain reaction (RTqPCR) assays, in order to determine if there was an expression correlation between these sources and to take advantage of the new information to be used in possible diagnosis by liquid biopsy. Data from these assays showed that platelets and breast cancer tumors present similar expression levels of a subset of these genes’ mRNAs, depending on the molecular subtype, comorbidities, and metastasis presence. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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14 pages, 1770 KiB

Open AccessArticle

Small-Molecule Cyclophilin Inhibitors Potently Reduce Platelet Procoagulant Activity

by Jens Van Bael, Aline Vandenbulcke, Abdelhakim Ahmed-Belkacem, Jean-François Guichou, Jean-Michel Pawlotsky, Jelle Samyn, Arjan D. Barendrecht, Coen Maas, Simon F. De Meyer, Karen Vanhoorelbeke and Claudia Tersteeg

Int. J. Mol. Sci. 2023, 24(8), 7163; https://doi.org/10.3390/ijms24087163 - 12 Apr 2023

Viewed by 1504

Abstract

Procoagulant platelets are associated with an increased risk for thrombosis. Procoagulant platelet formation is mediated via Cyclophilin D (CypD) mediated opening of the mitochondrial permeability transition pore. Inhibiting CypD activity could therefore be an interesting approach to limiting thrombosis. In this study, we [...] Read more.

Procoagulant platelets are associated with an increased risk for thrombosis. Procoagulant platelet formation is mediated via Cyclophilin D (CypD) mediated opening of the mitochondrial permeability transition pore. Inhibiting CypD activity could therefore be an interesting approach to limiting thrombosis. In this study, we investigated the potential of two novel, non-immunosuppressive, non-peptidic small-molecule cyclophilin inhibitors (SMCypIs) to limit thrombosis in vitro, in comparison with the cyclophilin inhibitor and immunosuppressant Cyclosporin A (CsA). Both cyclophilin inhibitors significantly decreased procoagulant platelet formation upon dual-agonist stimulation, shown by a decreased phosphatidylserine (PS) exposure, as well as a reduction in the loss of mitochondrial membrane potential. Furthermore, the SMCypIs potently reduced procoagulant platelet-dependent clotting time, as well as fibrin formation under flow, comparable to CsA. No effect was observed on agonist-induced platelet activation measured by P-selectin expression, as well as CypA-mediated integrin α_IIbβ₃ activation. Importantly, whereas CsA increased Adenosine 5′-diphosphate (ADP)-induced platelet aggregation, this was unaffected in the presence of the SMCypIs. We here demonstrate specific cyclophilin inhibition does not affect normal platelet function, while a clear reduction in procoagulant platelets is observed. Reducing platelet procoagulant activity by inhibiting cyclophilins with SMCypIs forms a promising strategy to limit thrombosis. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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13 pages, 3192 KiB

Open AccessArticle

Antiplatelet Effect of Daphnetin Is Regulated by cPLA₂-Mediated Thromboxane A₂ Generation in Mice

by Preeti Kumari Chaudhary, Sanggu Kim and Soochong Kim

Int. J. Mol. Sci. 2023, 24(6), 5779; https://doi.org/10.3390/ijms24065779 - 17 Mar 2023

Viewed by 1186

Abstract

Coumarin derivatives have been recognized for their antithrombotic, anti-inflammatory, and antioxidant properties, and daphnetin is one of the natural coumarin derivatives isolated from Daphne Koreana Nakai. Although the pharmacological value of daphnetin is well documented in diverse biological activities, its antithrombotic effect has [...] Read more.

Coumarin derivatives have been recognized for their antithrombotic, anti-inflammatory, and antioxidant properties, and daphnetin is one of the natural coumarin derivatives isolated from Daphne Koreana Nakai. Although the pharmacological value of daphnetin is well documented in diverse biological activities, its antithrombotic effect has not been studied to date. Here, we characterized the role and underlying mechanism of daphnetin in the regulation of platelet activation using murine platelets. In order to check the effect of daphnetin on platelet function, we first measured the effect of daphnetin on platelet aggregation and secretion. Collagen-induced platelet aggregation and dense granule secretion were partially inhibited by daphnetin. Interestingly, 2-MeSADP-induced secondary waves of aggregation and secretion were completely inhibited by daphnetin. It is known that 2-MeSADP-induced secretion and the resultant secondary wave of aggregation are mediated by the positive feedback effect of thromboxane A₂ (TxA₂) generation, suggesting the important role of daphnetin on TxA₂ generation in platelets. Consistently, daphnetin did not affect the 2-MeSADP-induced platelet aggregation in aspirinated platelets where the contribution of TxA₂ generation was blocked. Additionally, platelet aggregation and secretion induced by a low concentration of thrombin, which is affected by the positive feedback effect of TxA₂ generation, were partially inhibited in the presence of daphnetin. Importantly, 2-MeSADP- and thrombin-induced TxA₂ generation was significantly inhibited in the presence of daphnetin, confirming the role of daphnetin on TxA₂ generation. Finally, daphnetin significantly inhibited 2-MeSADP-induced cytosolic phospholipase A₂ (cPLA₂) and ERK phosphorylation in non-aspirinated platelets. Only cPLA₂ phosphorylation, not ERK phosphorylation, was significantly inhibited by daphnetin in aspirinated platelets. In conclusion, daphnetin plays a critical role in platelet function by inhibiting TxA₂ generation through the regulation of cPLA₂ phosphorylation. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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14 pages, 1136 KiB

Open AccessArticle

The Glycoprotein (GP)Ib-IX-V Complex on Platelets: GPIbα Protein Expression Is Reduced in HeartMate 3 Patients with Bleeding Complications within the First 3 Months

by Kristin Klaeske, Anneke Brade, Sandra Eifert, Khalil Jawad, Diyar Saeed, Josephina Haunschild, Franz Sieg, Michael A. Borger and Maja-Theresa Dieterlen

Int. J. Mol. Sci. 2023, 24(6), 5639; https://doi.org/10.3390/ijms24065639 - 15 Mar 2023

Viewed by 1186

Abstract

Non-surgical bleeding (NSB) remains the most critical complication in patients under left ventricular assist device (LVAD) support. It is well known that blood exposed to high shear stress results in platelet dysfunction. Compared to patients without NSB, decreased surface expression of platelet receptor [...] Read more.

Non-surgical bleeding (NSB) remains the most critical complication in patients under left ventricular assist device (LVAD) support. It is well known that blood exposed to high shear stress results in platelet dysfunction. Compared to patients without NSB, decreased surface expression of platelet receptor GPIbα was observed in LVAD patients with NSB. In this study, we aimed to compare the expression level of glycoprotein (GP)Ib-IX-V platelet receptor complex in HeartMate 3 (HM 3) patients with and without bleeding complications to investigate the alterations of the platelet transcriptomic profile on platelet damage and increased bleeding risk. Blood samples were obtained from HM 3 patients with NSB (bleeder group, n = 27) and without NSB (non-bleeder group, n = 55). The bleeder group was further divided into patients with early NSB (bleeder ≤ 3 mo, n = 19) and patients with late NSB (bleeder > 3 mo, n = 8). The mRNA and protein expression of GPIbα, GPIX and GPV were quantified for each patient. Non-bleeder, bleeder ≤ 3 mo and bleeder > 3 mo were comparable regarding the mRNA expression of GPIbα, GPIX and GPV (p > 0.05). The protein analysis revealed a significantly reduced expression level of the main receptor subunit GPIbα in bleeders ≤ 3 mo (p = 0.04). We suggest that the observed reduction of platelet receptor GPIbα protein expression in patients who experienced their first bleeding event within 3 months after LVAD implantation may influence platelet physiology. The alterations of functional GPIbα potentially reduce the platelet adhesion capacities, which may lead to an impaired hemostatic process and the elevated propensity of bleeding in HM 3 patients. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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22 pages, 2297 KiB

Open AccessArticle

SARS-CoV-2 Spike Protein and Neutralizing Anti-Spike Protein Antibodies Modulate Blood Platelet Function

by Boguslawa Luzak, Marcin Rozalski, Tomasz Przygodzki, Magdalena Boncler, Dagmara Wojkowska, Marcin Kosmalski and Cezary Watala

Int. J. Mol. Sci. 2023, 24(6), 5312; https://doi.org/10.3390/ijms24065312 - 10 Mar 2023

Cited by 1 | Viewed by 2117

Abstract

Several studies report elevated blood platelet activation and altered platelet count in COVID-19 patients, but the role of the SARS-CoV-2 spike protein in this process remains intriguing. Additionally, there is no data that anti-SARS-CoV-2 neutralizing antibodies (nAb) may attenuate spike protein activity toward [...] Read more.

Several studies report elevated blood platelet activation and altered platelet count in COVID-19 patients, but the role of the SARS-CoV-2 spike protein in this process remains intriguing. Additionally, there is no data that anti-SARS-CoV-2 neutralizing antibodies (nAb) may attenuate spike protein activity toward blood platelets. Our results indicate that under in vitro conditions, the spike protein increased the collagen-stimulated aggregation of isolated platelets and induced the binding of vWF to platelets in ristocetin-treated blood. The spike protein also significantly reduced collagen- or ADP-induced aggregation or decreased GPIIbIIIa (fibrinogen receptor) activation in whole blood, depending on the presence of the anti-spike protein nAb. Our findings suggest that studies on platelet activation/reactivity in COVID-19 patients or in donors vaccinated with anti-SARS-CoV-2 and/or previously-infected COVID-19 should be supported by measurements of spike protein and IgG anti-spike protein antibody concentrations in blood. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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10 pages, 1482 KiB

Open AccessArticle

Long-Term Results of Adjunct Autologous Platelet-Rich Plasma in Lamellar Macular Hole Surgery Showing Lasting Restoration of Foveal Anatomy

by Felix Hagenau, Elisa V. Osterode, Julian E. Klaas, Denise Vogt, Leonie F. Keidel, Benedikt Schworm, Jakob Siedlecki, Wolfgang J. Mayer, Thomas C. Kreutzer and Siegfried G. Priglinger

Int. J. Mol. Sci. 2023, 24(5), 4589; https://doi.org/10.3390/ijms24054589 - 27 Feb 2023

Cited by 2 | Viewed by 1368

Abstract

The aim of this study was to evaluate the long-time results of highly concentrated autologous platelet-rich plasma (PRP) used as an adjunct in lamellar macular hole (LMH) surgery. Nineteen eyes of nineteen patients with progressive LMH were enrolled in this interventional case series, [...] Read more.

The aim of this study was to evaluate the long-time results of highly concentrated autologous platelet-rich plasma (PRP) used as an adjunct in lamellar macular hole (LMH) surgery. Nineteen eyes of nineteen patients with progressive LMH were enrolled in this interventional case series, on which 23/25-gauge pars plana vitrectomy was performed and 0.1 mL of highly concentrated autologous platelet-rich plasma was applied under air tamponade. Posterior vitreous detachment was induced, and the peeling of tractive epiretinal membranes, whenever present, was performed. In cases of phakic lens status, combined surgery was carried out. Postoperatively, all patients were instructed to remain in a supine position for the first two postoperative hours. Best-corrected visual acuity (BCVA) testing, microperimetry, and spectral domain optical coherence tomography (SD-OCT) were carried out preoperatively and at minimum 6 months (in median 12 months) postoperatively. Foveal configuration was postoperatively restored in 19 of 19 patients. Two patients who had not undergone ILM peeling showed a recurring defect at 6-month follow-up. Best-corrected visual acuity improved significantly from 0.29 ± 0.08 to 0.14 ± 0.13 logMAR (p = 0.028, Wilcoxon signed-rank test). Microperimetry remained unchanged (23.38 ± 2.53 preoperatively; 23.0 ± 2.49 dB postoperatively; p = 0.67). No patients experienced vision loss after surgery, and no significant intra- or postoperative complications were observed. Using PRP as an adjunct in macular hole surgery significantly improves morphological and functional outcomes. Additionally, it might be an effective prophylaxis to further progression and also the formation of a secondary full-thickness macular hole. The results of this study might contribute to a paradigm shift in macular hole surgery towards early intervention. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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21 pages, 13001 KiB

Open AccessArticle

Structure–Activity Relationship Analysis of Rhosin, a RhoA GTPase Inhibitor, Reveals a New Class of Antiplatelet Agents

by Akhila Dandamudi, William Seibel, Benjamin Tourdot, Jose A. Cancelas, Huzoor Akbar and Yi Zheng

Int. J. Mol. Sci. 2023, 24(4), 4167; https://doi.org/10.3390/ijms24044167 - 19 Feb 2023

Viewed by 1808

Abstract

Current antiplatelet therapies have several clinical complications and are mostly irreversible in terms of suppressing platelet activity; hence, there is a need to develop improved therapeutic agents. Previous studies have implicated RhoA in platelet activation. Here, we further characterized the lead RhoA inhibitor, [...] Read more.

Current antiplatelet therapies have several clinical complications and are mostly irreversible in terms of suppressing platelet activity; hence, there is a need to develop improved therapeutic agents. Previous studies have implicated RhoA in platelet activation. Here, we further characterized the lead RhoA inhibitor, Rhosin/G04, in platelet function and present structure–activity relationship (SAR) analysis. A screening for Rhosin/G04 analogs in our chemical library by similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. A screening for Rhosin/G04 analogs in our chemical library using similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. SAR analysis revealed that the active compounds have a quinoline group optimally attached to the hydrazine at the 4-position and halogen substituents at the 7- or 8-position. Having indole, methylphenyl, or dichloro-phenyl substituents led to better potency. Rhosin/G04 contains a pair of enantiomers, and S-G04 is significantly more potent than R-G04 in inhibiting RhoA activation and platelet aggregation. Furthermore, the inhibitory effect is reversible, and S-G04 is capable of inhibiting diverse-agonist-stimulated platelet activation. This study identified a new generation of small-molecule RhoA inhibitors, including an enantiomer capable of broadly and reversibly modulating platelet activity. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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15 pages, 2807 KiB

Open AccessArticle

LL-37 Triggers Antimicrobial Activity in Human Platelets

by Francisco Javier Sánchez-Peña, María de los Ángeles Romero-Tlalolini, Honorio Torres-Aguilar, Diego Sait Cruz-Hernández, Rafael Baltiérrez-Hoyos, Saraí Remedios Sánchez-Aparicio, Alba Soledad Aquino-Domínguez and Sergio Roberto Aguilar-Ruiz

Int. J. Mol. Sci. 2023, 24(3), 2816; https://doi.org/10.3390/ijms24032816 - 01 Feb 2023

Cited by 3 | Viewed by 2257

Abstract

Platelets play a crucial role in hemostasis and the immune response, mainly by recognizing signals associated with vascular damage. However, it has recently been discovered that the antimicrobial peptide LL-37 activates platelets in functions related to thrombus formation and inflammation. Therefore, this work [...] Read more.

Platelets play a crucial role in hemostasis and the immune response, mainly by recognizing signals associated with vascular damage. However, it has recently been discovered that the antimicrobial peptide LL-37 activates platelets in functions related to thrombus formation and inflammation. Therefore, this work aims to evaluate the effect of LL-37 on the activation of antimicrobial functions of human platelets. Our results show that platelets treated with LL-37 increase the surface expression of receptors (Toll-like receptors (TLRs) 2 and -4, CD32, CD206, Dectin-1, CD35, LOX-1, CD41, CD62P, and αIIbβ3 integrins) for the recognition of microorganisms, and molecules related to antigen presentation to T lymphocytes (CD80, CD86, and HLA-ABC) secrete the antimicrobial molecules: bactericidal/permeability-increasing protein (BPI), azurocidin, human neutrophil peptide (HNP) -1, and myeloperoxidase. They also translate azurocidin, and have enhanced binding to Escherichia coli, Staphylococcus aureus, and Candida albicans. Furthermore, the supernatant of LL-37-treated platelets can inhibit E. coli growth, or platelets can employ their LL-37 to inhibit microbial growth. In conclusion, these findings demonstrate that LL-37 participates in the antimicrobial function of human platelets. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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19 pages, 2137 KiB

Open AccessArticle

In Vitro Comparison of Lymphangiogenic Potential of Hypoxia Preconditioned Serum (HPS) and Platelet-Rich Plasma (PRP)

by Jun Jiang, Xiaobin Cong, Sarah Alageel, Ulf Dornseifer, Arndt F. Schilling, Ektoras Hadjipanayi, Hans-Günther Machens and Philipp Moog

Int. J. Mol. Sci. 2023, 24(3), 1961; https://doi.org/10.3390/ijms24031961 - 19 Jan 2023

Cited by 4 | Viewed by 1873

Abstract

Strategies for therapeutic lymphangiogenesis are gradually directed toward the use of growth factor preparations. In particular, blood-derived growth factor products, including Hypoxia Preconditioned Serum (HPS) and Platelet-rich Plasma (PRP), are both clinically employed for accelerating tissue repair and have received considerable attention in [...] Read more.

Strategies for therapeutic lymphangiogenesis are gradually directed toward the use of growth factor preparations. In particular, blood-derived growth factor products, including Hypoxia Preconditioned Serum (HPS) and Platelet-rich Plasma (PRP), are both clinically employed for accelerating tissue repair and have received considerable attention in the field of regenerative medicine research. In this study, a comparative analysis of HPS and PRP was conducted to explore their lymphangiogenic potential. We found higher pro-lymphangiogenic growth factor concentrations of VEGF-C, PDGF-BB, and bFGF in HPS in comparison to normal serum (NS) and PRP. The proliferation and migration of lymphatic endothelial cells (LECs) were promoted considerably with both HPS and PRP, but the strongest effect was achieved with HPS-40% dilution. Tube formation of LECs showed the highest number of tubes, branching points, greater tube length, and cell-covered area with HPS-10%. Finally, the effects were double-validated using an ex vivo lymphatic ring assay, in which the highest number of sprouts and the greatest sprout length were achieved with HPS-10%. Our findings demonstrate the superior lymphangiogenic potential of a new generation blood-derived secretome obtained by hypoxic preconditioning of peripheral blood cells—a method that offers a novel alternative to PRP. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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15 pages, 305 KiB

Open AccessArticle

Plasma Concentration of Cortisol Negatively Associates with Platelet Reactivity in Older Subjects

by Kamil Karolczak, Lucyna Konieczna, Bartlomiej Soltysik, Tomasz Kostka, Piotr Jakub Witas, Joanna Kostanek, Tomasz Baczek and Cezary Watala

Int. J. Mol. Sci. 2023, 24(1), 717; https://doi.org/10.3390/ijms24010717 - 31 Dec 2022

Cited by 4 | Viewed by 1366

Abstract

The interaction of platelets with steroid hormones is poorly investigated. Age is one of the factors that increase the risk of pathological platelet reactivity and thrombosis. The aim of this study was to assess whether there were associations between platelet reactivity and plasma [...] Read more.

The interaction of platelets with steroid hormones is poorly investigated. Age is one of the factors that increase the risk of pathological platelet reactivity and thrombosis. The aim of this study was to assess whether there were associations between platelet reactivity and plasma cortisol levels in volunteers aged 60–65 years. For this purpose, impedance aggregometry in whole blood measured after arachidonic acid, collagen, or ADP stimulation was used to estimate platelet reactivity and mass spectrometry was used to measure peripheral plasma cortisol concentration. Statistically significant negative correlations were observed between cortisol concentration and platelet reactivity in response to arachidonic acid and ADP, but not to collagen. The presented results suggest for the very first time that cortisol is a new endogenous modulator of platelet reactivity in the elderly population. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

18 pages, 3675 KiB

Open AccessArticle

Transcription Factors STAT3 and MYC Are Key Players of Human Platelet Lysate-Induced Cell Proliferation

by Michaela Oeller, Heidi Jaksch-Bogensperger, Markus Templin, Renate Gehwolf, Eva Rohde, Katharina Schallmoser and Sandra Laner-Plamberger

Int. J. Mol. Sci. 2022, 23(24), 15782; https://doi.org/10.3390/ijms232415782 - 13 Dec 2022

Cited by 2 | Viewed by 1538

Abstract

Human platelet lysate (HPL) is an efficient alternative for animal serum supplements, significantly enhancing stromal cell proliferation. However, the molecular mechanism behind this growth-promoting effect remains elusive. The aim of this study was to investigate the effect of HPL on cell cycle gene [...] Read more.

Human platelet lysate (HPL) is an efficient alternative for animal serum supplements, significantly enhancing stromal cell proliferation. However, the molecular mechanism behind this growth-promoting effect remains elusive. The aim of this study was to investigate the effect of HPL on cell cycle gene expression in different human stromal cells and to identify the main key players that mediate HPL’s growth-enhancing effect. RT-qPCR and an antibody array revealed significant upregulation of cell cycle genes in stromal cells cultured in HPL. As HPL is rich in growth factors that are ligands of tyrosine kinase receptor (TKR) pathways, we used TKR inhibitors and could significantly reduce cell proliferation. Genome profiling, RT-qPCR and Western blotting revealed an enhanced expression of the transcription factors signal transducer and activator of transcription 3 (STAT3) and MYC, both known TKR downstream effectors and stimulators of cell proliferation, in response to HPL. In addition, specifically blocking STAT3 resulted in reduced cell proliferation and expression of cell cycle genes. Our data indicate that HPL-enhanced cell proliferation can, at least in part, be explained by the TKR-enhanced expression of STAT3 and MYC, which in turn induce the expression of genes being involved in the promotion and control of the cell cycle. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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14 pages, 3633 KiB

Open AccessArticle

Platelet Reactivity and Inflammatory Phenotype Induced by Full-Length Spike SARS-CoV-2 Protein and Its RBD Domain

by Alan Cano-Mendez, Nallely García-Larragoiti, Maria Damian-Vazquez, Patricia Guzman-Cancino, Sandra Lopez-Castaneda, Alejandra Ochoa-Zarzosa and Martha Eva Viveros-Sandoval

Int. J. Mol. Sci. 2022, 23(23), 15191; https://doi.org/10.3390/ijms232315191 - 02 Dec 2022

Cited by 1 | Viewed by 1306

Abstract

A state of immunothrombosis has been reported in COVID-19. Platelets actively participate in this process. However, little is known about the ability of SARS-CoV-2 virus proteins to induce platelet activity. Platelet-rich plasma (PRP) was incubated with spike full-length protein and the RBD domain [...] Read more.

A state of immunothrombosis has been reported in COVID-19. Platelets actively participate in this process. However, little is known about the ability of SARS-CoV-2 virus proteins to induce platelet activity. Platelet-rich plasma (PRP) was incubated with spike full-length protein and the RBD domain in independent assays. We evaluated platelet activation through the expression of P-selectin and activation of glicoprotein IIbIIIa (GP IIbIIIa), determined by flow cytometry and the ability of the proteins to induce platelet aggregation. We determined concentrations of immunothrombotic biomarkers in PRP supernatant treated with the proteins. We determined that the spike full-length proteins and the RBD domain induced an increase in P-selectin expression and GP IIbIIIa activation (p < 0.0001). We observed that the proteins did not induce platelet aggregation, but favored a pro-aggregating state that, in response to minimal doses of collagen, could re-establish the process (p < 0.0001). On the other hand, the viral proteins stimulated the release of interleukin 6, interleukin 8, P-selectin and the soluble fraction of CD40 ligand (sCD40L), molecules that favor an inflammatory state p < 0.05. These results indicate that the spike full-length protein and its RBD domain can induce platelet activation favoring an inflammatory phenotype that might contribute to the development of an immunothrombotic state. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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16 pages, 1196 KiB

Open AccessArticle

Evaluation of Circulating Platelet Extracellular Vesicles and Hypertension Mediated Organ Damage

by Leslie Marisol Lugo-Gavidia, Dylan Burger, Janis M. Nolde, Vance B. Matthews and Markus P. Schlaich

Int. J. Mol. Sci. 2022, 23(23), 15150; https://doi.org/10.3390/ijms232315150 - 02 Dec 2022

Viewed by 2112

Abstract

Elevated circulating platelet-derived extracellular vesicles (pEVs) have been associated with arterial hypertension. The role of hypertension-mediated organ damage (HMOD) to induce EV release is still unknown. We studied the micro- and macro-vascular changes (retinal vascular density and pulse wave velocity), endothelial function (flow-mediated [...] Read more.

Elevated circulating platelet-derived extracellular vesicles (pEVs) have been associated with arterial hypertension. The role of hypertension-mediated organ damage (HMOD) to induce EV release is still unknown. We studied the micro- and macro-vascular changes (retinal vascular density and pulse wave velocity), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), and assessed the psychosocial status (anxiety and depression) in hypertensive patients to determine their relationship with EV release. Pulse wave velocity showed a significant positive correlation with pEVs (r = 0.33; p = 0.01). Systolic blood pressure (SBP) negatively correlated with retinal vascularity. The superficial retinal vascular plexus density in the whole image showed a significant negative correlation with 24 h SBP (r = −0.38, p < 0.01), day-SBP (r = −0.35, p = 0.01), and night-SBP (r = −0.27, p = 0.04). pEVs did not show significant associations with microvascular damage (retinal vascular density), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), or psychosocial status (anxiety and depression). Our results indicate that the pEV levels were associated with macrovascular damage measured by PWV, whereas no significant association between pEVs and microvascular damage, endothelial function, or emotional status could be detected. The potential utility of pEV in clinical practice in the context of HMOD may be limited to macrovascular changes. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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14 pages, 2539 KiB

Open AccessArticle

Relationship between the Responsiveness of Amyloid β Protein to Platelet Activation by TRAP Stimulation and Brain Atrophy in Patients with Diabetes Mellitus

by Takamitsu Hori, Daisuke Mizutani, Takashi Onuma, Yu Okada, Kumi Kojima, Tomoaki Doi, Yukiko Enomoto, Hiroki Iida, Shinji Ogura, Takashi Sakurai, Toru Iwama, Osamu Kozawa and Haruhiko Tokuda

Int. J. Mol. Sci. 2022, 23(22), 14100; https://doi.org/10.3390/ijms232214100 - 15 Nov 2022

Viewed by 1326

Abstract

Type 2 DM is a risk factor for dementia, including Alzheimer’s disease (AD), and is associated with brain atrophy. Amyloid β protein (Aβ) deposition in the brain parenchyma is implicated in the neurodegeneration that occurs in AD. Platelets, known as abundant storage of [...] Read more.

Type 2 DM is a risk factor for dementia, including Alzheimer’s disease (AD), and is associated with brain atrophy. Amyloid β protein (Aβ) deposition in the brain parenchyma is implicated in the neurodegeneration that occurs in AD. Platelets, known as abundant storage of Aβ, are recognized to play important roles in the onset and progression of AD. We recently showed that Aβ negatively regulates platelet activation induced by thrombin receptor-activating protein (TRAP) in healthy people. In the present study, we investigated the effects of Aβ on the TRAP-stimulated platelet activation in DM patients, and the relationship between the individual responsiveness to Aβ and quantitative findings of MRI, the volume of white matter hyperintensity (WMH)/intracranial volume (IC) and the volume of parenchyma (PAR)/IC. In some DM patients, Aβ reduced platelet aggregation induced by TRAP, while in others it was unchanged or rather enhanced. The TRAP-induced levels of phosphorylated-Akt and phosphorylated-HSP27, the levels of PDGF-AB and the released phosphorylated-HSP27 correlated with the degree of platelet aggregability. The individual levels of not WMH/IC but PAR/IC was correlated with those of TRAP-stimulated PDGF-AB release. Collectively, our results suggest that the reactivity of TRAP-stimulated platelet activation to Aβ differs in DM patients from healthy people. The anti-suppressive feature of platelet activation to Aβ might be protective for brain atrophy in DM patients. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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18 pages, 5014 KiB

Open AccessArticle

Blockade of Platelet CysLT1R Receptor with Zafirlukast Counteracts Platelet Protumoral Action and Prevents Breast Cancer Metastasis to Bone and Lung

by Lou Saier, Johnny Ribeiro, Thomas Daunizeau, Audrey Houssin, Gabriel Ichim, Caroline Barette, Lamia Bouazza and Olivier Peyruchaud

Int. J. Mol. Sci. 2022, 23(20), 12221; https://doi.org/10.3390/ijms232012221 - 13 Oct 2022

Viewed by 1976

Abstract

Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is highly challenging given their paramount function in hemostasis. Using a high-throughput screening and platelet-induced breast tumor cell survival [...] Read more.

Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is highly challenging given their paramount function in hemostasis. Using a high-throughput screening and platelet-induced breast tumor cell survival (PITCS) assay as endpoint, we identified the widely used anti-asthmatic drugs and cysteinyl leukotriene receptor 1 (CysLT1R) antagonists, zafirlukast and montelukast, as new specific blockers of platelet protumoral action. Here, we show that human MDA-B02 breast cancer cells produce CysLT through mechanisms involving microsomal glutathione-S-transferase 1/2/3 (MGST1/2/3) and that can modulate cancer cell–platelet interactions via platelet–CysLT1R. CysLT1R blockade with zafirlukast decreased platelet aggregation and adhesion on cancer cells and inhibited PITCS, migration, and invasion in vitro. Zafirlukast significantly reduced, by 90%, MDA-B02 cell dissemination to bone in nude mice and reduced by 88% 4T1 spontaneous lung metastasis formation without affecting primary tumor growth. Combined treatment of zafirlukast plus paclitaxel totally inhibited metastasis of 4T1 cells to the lungs. Altogether, our results reveal a novel pathway mediating the crosstalk between cancer cells and platelets and indicate that platelet CysLT1R represents a novel therapeutic target to prevent metastasis without affecting hemostasis. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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12 pages, 990 KiB

Open AccessArticle

Association of Circulating Platelet Extracellular Vesicles and Pulse Wave Velocity with Cardiovascular Risk Estimation

by Leslie Marisol Lugo-Gavidia, Janis M. Nolde, Revathy Carnagarin, Dylan Burger, Justine Chan, Sandi Robinson, Erika Bosio, Vance B. Matthews and Markus P. Schlaich

Int. J. Mol. Sci. 2022, 23(18), 10524; https://doi.org/10.3390/ijms231810524 - 10 Sep 2022

Cited by 1 | Viewed by 1349

Abstract

Elevated circulating platelet-derived extracellular vesicles (EVs) have been reported in conditions associated with thrombotic risk. The present study aimed to assess the relationship between circulating platelet-derived EV levels, cardiovascular risk stratification and vascular organ damage, as assessed by pulse wave velocity (PWV). A [...] Read more.

Elevated circulating platelet-derived extracellular vesicles (EVs) have been reported in conditions associated with thrombotic risk. The present study aimed to assess the relationship between circulating platelet-derived EV levels, cardiovascular risk stratification and vascular organ damage, as assessed by pulse wave velocity (PWV). A total of 92 patients were included in the present analysis. Platelet EV were evaluated by flow cytometry (CD41+/Annexin v+). The cardiovascular risk was determined using the 2021 ESC guideline stratification and SCORE2 and SCORE-OP. PWV was performed as a surrogate to assess macrovascular damage. Risk stratification revealed significant group differences in EV levels (ANOVA, p = 0.04). Post hoc analysis demonstrated significantly higher levels of EVs in the very high-risk group compared with the young participants (12.53 ± 8.69 vs. 7.51 ± 4.67 EV/µL, p = 0.03). Linear regression models showed SCORE2 and SCORE-OP (p = 0.04) was a predictor of EV levels. EVs showed a significant association with macrovascular organ damage measured by PWV (p = 0.01). PWV progressively increased with more severe cardiovascular risk (p < 0.001) and was also associated with SCORE2 and SCORE-OP (p < 0.001). Within the pooled group of subjects with low to moderate risk and young participants (<40 years), those with EV levels in the highest tertile had a trend towards higher nocturnal blood pressure levels, fasting glucose concentration, lipid levels, homocysteine and PWV. Levels of platelet-derived EVs were highest in those patients with very high CV risk. Within a pooled group of patients with low to moderate risk, an unfavourable cardiometabolic profile was present with higher EV levels. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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Review

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12 pages, 1311 KiB

Open AccessReview

The Immunological Capacity of Thrombocytes

by Farzana Ferdous and Thomas Scott

Int. J. Mol. Sci. 2023, 24(16), 12950; https://doi.org/10.3390/ijms241612950 - 18 Aug 2023

Cited by 1 | Viewed by 1319

Abstract

Thrombocytes are numerous in the blood of aves (birds) and ichthyoids (fish). The origin of this cell type is a common hematopoietic stem cell giving rise to a cell that is active in blood coagulation, inflammatory functions, and the immune response in general. [...] Read more.

Thrombocytes are numerous in the blood of aves (birds) and ichthyoids (fish). The origin of this cell type is a common hematopoietic stem cell giving rise to a cell that is active in blood coagulation, inflammatory functions, and the immune response in general. It has been well documented that thrombocytes can phagocytize small particles and bacteria. While phagocytosis with an associated oxidative burst has been reported for chicken thrombocytes, some questions remain as to the degradation capacity of phagosomes in ichthyoids. As innate cells, thrombocytes can be stimulated by bacterial, viral, and fungal pathogens to express altered gene expression. Furthermore, there have been observations that led researchers to state that platelets/thrombocytes are capable of serving as “professional antigen presenting cells” expressing CD40, CD80/86, MHC I, and MHC II. This indeed may be the case or, more likely at this time, provide supporting evidence that these cells aid and assist in the role of professional antigen-presenting cells to initiate adaptive immune responses. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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23 pages, 421 KiB

Open AccessReview

Pro-Tumorigenic and Thrombotic Activities of Platelets in Lung Cancer

by Ronald Anderson, Bernardo L. Rapoport, Helen C. Steel and Annette J. Theron

Int. J. Mol. Sci. 2023, 24(15), 11927; https://doi.org/10.3390/ijms241511927 - 25 Jul 2023

Viewed by 1225

Abstract

Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis, progression and outcome of many types of human malignancy. The most consistent and compelling evidence in this context has been [...] Read more.

Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis, progression and outcome of many types of human malignancy. The most consistent and compelling evidence in this context has been derived from the notable association of elevated circulating platelet counts with the onset and prognosis of various human malignancies, particularly lung cancer, which represents the primary focus of the current review. Key topics include an overview of the association of lung cancer with the circulating platelet count, as well as the mechanisms of platelet-mediated, pro-tumorigenic immunosuppression, particularly the role of transforming growth factor beta 1. These issues are followed by a discussion regarding the pro-tumorigenic role of platelet-derived microparticles (PMPs), the most abundant type of microparticles (MPs) in human blood. In this context, the presence of increased levels of PMPs in the blood of lung cancer patients has been associated with tumor growth, invasion, angiogenesis and metastasis, which correlate with disease progression and decreased survival times. The final section of the review addresses, firstly, the role of cancer-related platelet activation and thrombosis in the pathogenesis of secondary cardiovascular disorders and the associated mortality, particularly in lung cancer, which is second only to disease progression; secondly, the review addresses the potential role of antiplatelet agents in the adjunctive therapy of cancer. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

14 pages, 2126 KiB

Open AccessReview

The Effects of Statins, Ezetimibe, PCSK9-Inhibitors, Inclisiran, and Icosapent Ethyl on Platelet Function

by Assunta Di Costanzo, Ciro Indolfi, Sabato Sorrentino, Giovanni Esposito and Carmen Anna Maria Spaccarotella

Int. J. Mol. Sci. 2023, 24(14), 11739; https://doi.org/10.3390/ijms241411739 - 21 Jul 2023

Cited by 1 | Viewed by 3036

Abstract

This review aims to examine the complex interaction between dyslipidemia, platelet function, and related drug treatments. In particular, the manuscript provides an overview of the effects of major hypolipidemic drugs on platelet function. Indeed, growing evidence supports the view that statins, ezetimibe, PCSK9 [...] Read more.

This review aims to examine the complex interaction between dyslipidemia, platelet function, and related drug treatments. In particular, the manuscript provides an overview of the effects of major hypolipidemic drugs on platelet function. Indeed, growing evidence supports the view that statins, ezetimibe, PCSK9 inhibitors, inclisiran, and icosapent ethyl also act as antithrombotics. It is known that platelets play a key role not only in the acute phase of coronary syndromes but also in the early phase of atherosclerotic plaque formation. The goal of cholesterol-lowering therapy is to reduce cardiovascular events. The direct effects of cholesterol-lowering drugs are widely described in the literature. Lowering LDL-c (low-density lipoprotein cholesterol) by 1 mmol/L results in a 22–23% reduction in cardiovascular risk. Numerous studies have examined the direct antithrombotic effects of these drugs on platelets, endothelium, monocytes, and smooth muscle cells, and thus, potentially independent of blood LDL-cholesterol reduction. We reviewed in vitro and in vivo studies evaluating the complex interaction between hypercholesterolemia, hypertriglyceridemia, platelet function, and related drug treatments. First, we discussed the role of statins in modulating platelet activation. Discontinuation of statin therapy was associated with increased cardiovascular events with increased ox-LDL, P-selectin, and platelet aggregation. The effect of PCSK9-I (inhibitors of proprotein convertase subtilisin/kexin type 9, PCSK9 involved in the degradation of LDL receptors in the liver) was associated with a statistically significant reduction in platelet reactivity, calculated in P2Y12 reaction units (PRU), in the first 14 days and no difference at 30 days compared to placebo. Finally, in patients with hypertriglyceridemia, the REDUCE-IT study showed that icosapent ethyl (an ethyl ester of eicosapentaenoic acid that reduces triglyceride synthesis and improves triglyceride clearance) resulted in a 25% reduction in ischemic events and cardiovascular death. However, to date, there is not yet clear clinical evidence that the direct antithrombotic effects of the drugs may have a beneficial impact on outcomes independently from the reduction in LDL-C or triglycerides. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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14 pages, 3199 KiB

Open AccessReview

Individualized or Uniform De-Escalation Strategies for Antiplatelet Therapy in Acute Coronary Syndrome: A Review of Clinical Trials with Platelet Function Testing and Genetic Testing-Based Protocols

by Oumaima El Alaoui El Abdallaoui, Dániel Tornyos, Réka Lukács, Dóra Szabó and András Komócsi

Int. J. Mol. Sci. 2023, 24(10), 9071; https://doi.org/10.3390/ijms24109071 - 22 May 2023

Cited by 2 | Viewed by 1248

Abstract

This comprehensive literature review assessed the effectiveness of precision medicine approaches in individualizing P2Y12 de-escalation strategies, such as platelet function testing guidance, genetic testing guidance, and uniform de-escalation, for acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Analyzing six trials with [...] Read more.

This comprehensive literature review assessed the effectiveness of precision medicine approaches in individualizing P2Y12 de-escalation strategies, such as platelet function testing guidance, genetic testing guidance, and uniform de-escalation, for acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Analyzing six trials with a total of 13,729 patients, the cumulative analyses demonstrated a significant reduction in major adverse cardiac events (MACE), net adverse clinical events (NACE), and major and minor bleeding events with P2Y12 de-escalation. Specifically, the analysis found a 24% reduction of MACE and a 22% reduction of adverse event risk (relative risk (RR) 0.76, 95% confidence interval (CI): 0.71–0.82, and RR: 0.78, 95% CI 0.67–0.92, respectively). Reductions in bleeding events were highest with uniform unguided de-escalation, followed by guided de-escalations, while ischemic event rates were similarly lower across all three strategies. Although the review highlights the potential of individualized P2Y12 de-escalation strategies to offer a safer alternative to the long-term potent P2Y12 inhibitor-based dual antiplatelet therapy, it also indicates that laboratory-guided precision medicine approaches may not yet offer the expected benefits, necessitating further research to optimize individualized strategies and evaluate the potential of precision medicine approaches in this context. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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13 pages, 1060 KiB

Open AccessReview

Novel Knowledge about Molecular Mechanisms of Heparin-Induced Thrombocytopenia Type II and Treatment Targets

by Aušra Mongirdienė, Agnė Liuizė and Artūras Kašauskas

Int. J. Mol. Sci. 2023, 24(9), 8217; https://doi.org/10.3390/ijms24098217 - 04 May 2023

Cited by 2 | Viewed by 2056

Abstract

Heparin-induced thrombocytopenia type II (HIT II), as stated in the literature, occurs in about 3% of all patients and in 0.1–5% of surgical patients. Thrombosis develops in 20–64% of patients with HIT. The mortality rate in HIT II has not decreased using non-heparin [...] Read more.

Heparin-induced thrombocytopenia type II (HIT II), as stated in the literature, occurs in about 3% of all patients and in 0.1–5% of surgical patients. Thrombosis develops in 20–64% of patients with HIT. The mortality rate in HIT II has not decreased using non-heparin treatment with anticoagulants such as argatroban and lepirudin. An improved understanding of the pathophysiology of HIT may help identify targeted therapies to prevent thrombosis without subjecting patients to the risk of intense anticoagulation. The review will summarize the current knowledge about the pathogenesis of HIT II, potential new therapeutic targets related to it, and new treatments being developed. HIT II pathogenesis involves multi-step immune-mediated pathways dependent on the ratio of PF4/heparin and platelet, monocyte, neutrophil, and endothelium activation. For years, only platelets were known to take part in HIT II development. A few years ago, specific receptors and signal-induced pathways in monocytes, neutrophils and endothelium were revealed. It had been shown that the cells that had become active realised different newly formed compounds (platelet-released TF, TNFα, NAP2, CXCL-7, ENA-78, platelet-derived microparticles; monocytes-TF-MPs; neutrophils-NETs), leading to additional cell activation and consequently thrombin generation, resulting in thrombosis. Knowledge about FcγIIa receptors on platelets, monocytes, neutrophils and FcγIIIa on endothelium, chemokine (CXCR-2), and PSGL-1 receptors on neutrophils could allow for the development of a new non-anticoagulant treatment for HIT II. IgG degradation, Syk kinase and NETosis inhibition are in the field of developing new treatment possibilities too. Accordingly, IdeS and DNases-related pathways should be investigated for better understanding of HIT pathogenesis and the possibilities of being the HIT II treatment targets. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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31 pages, 2133 KiB

Open AccessReview

Platelets, Protean Cells with All-Around Functions and Multifaceted Pharmacological Applications

by Chiara Puricelli, Elena Boggio, Casimiro Luca Gigliotti, Ian Stoppa, Salvatore Sutti, Mara Giordano, Umberto Dianzani and Roberta Rolla

Int. J. Mol. Sci. 2023, 24(5), 4565; https://doi.org/10.3390/ijms24054565 - 26 Feb 2023

Cited by 7 | Viewed by 2539

Abstract

Platelets, traditionally known for their roles in hemostasis and coagulation, are the most prevalent blood component after erythrocytes (150,000–400,000 platelets/μL in healthy humans). However, only 10,000 platelets/μL are needed for vessel wall repair and wound healing. Increased knowledge of the platelet’s role in [...] Read more.

Platelets, traditionally known for their roles in hemostasis and coagulation, are the most prevalent blood component after erythrocytes (150,000–400,000 platelets/μL in healthy humans). However, only 10,000 platelets/μL are needed for vessel wall repair and wound healing. Increased knowledge of the platelet’s role in hemostasis has led to many advances in understanding that they are crucial mediators in many other physiological processes, such as innate and adaptive immunity. Due to their multiple functions, platelet dysfunction is involved not only in thrombosis, mediating myocardial infarction, stroke, and venous thromboembolism, but also in several other disorders, such as tumors, autoimmune diseases, and neurodegenerative diseases. On the other hand, thanks to their multiple functions, nowadays platelets are therapeutic targets in different pathologies, in addition to atherothrombotic diseases; they can be used as an innovative drug delivery system, and their derivatives, such as platelet lysates and platelet extracellular vesicles (pEVs), can be useful in regenerative medicine and many other fields. The protean role of platelets, from the name of Proteus, a Greek mythological divinity who could take on different shapes or aspects, is precisely the focus of this review. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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15 pages, 1579 KiB

Open AccessReview

Rho GTPase Signaling in Platelet Regulation and Implication for Antiplatelet Therapies

by Akhila Dandamudi, Huzoor Akbar, Jose Cancelas and Yi Zheng

Int. J. Mol. Sci. 2023, 24(3), 2519; https://doi.org/10.3390/ijms24032519 - 28 Jan 2023

Cited by 1 | Viewed by 3441

Abstract

Platelets play a vital role in regulating hemostasis and thrombosis. Rho GTPases are well known as molecular switches that control various cellular functions via a balanced GTP-binding/GTP-hydrolysis cycle and signaling cascade through downstream effectors. In platelets, Rho GTPases function as critical regulators by [...] Read more.

Platelets play a vital role in regulating hemostasis and thrombosis. Rho GTPases are well known as molecular switches that control various cellular functions via a balanced GTP-binding/GTP-hydrolysis cycle and signaling cascade through downstream effectors. In platelets, Rho GTPases function as critical regulators by mediating signal transduction that drives platelet activation and aggregation. Mostly by gene targeting and pharmacological inhibition approaches, Rho GTPase family members RhoA, Rac1, and Cdc42 have been shown to be indispensable in regulating the actin cytoskeleton dynamics in platelets, affecting platelet shape change, spreading, secretion, and aggregation, leading to thrombus formation. Additionally, studies of Rho GTPase function using platelets as a non-transformed model due to their anucleated nature have revealed valuable information on cell signaling principles. This review provides an updated summary of recent advances in Rho GTPase signaling in platelet regulation. We also highlight pharmacological approaches that effectively inhibited platelet activation to explore their possible development into future antiplatelet therapies. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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14 pages, 812 KiB

Open AccessReview

Dissecting Platelet’s Role in Viral Infection: A Double-Edged Effector of the Immune System

by Hajar El Filaly, Meryem Mabrouk, Farah Atifi, Fadila Guessous, Khadija Akarid, Yahye Merhi and Younes Zaid

Int. J. Mol. Sci. 2023, 24(3), 2009; https://doi.org/10.3390/ijms24032009 - 19 Jan 2023

Cited by 3 | Viewed by 2763

Abstract

Platelets play a major role in the processes of primary hemostasis and pathological inflammation-induced thrombosis. In the mid-2000s, several studies expanded the role of these particular cells, placing them in the “immune continuum” and thus changing the understanding of their function in both [...] Read more.

Platelets play a major role in the processes of primary hemostasis and pathological inflammation-induced thrombosis. In the mid-2000s, several studies expanded the role of these particular cells, placing them in the “immune continuum” and thus changing the understanding of their function in both innate and adaptive immune responses. Among the many receptors they express on their surface, platelets express Toll-Like Receptors (TLRs), key receptors in the inflammatory cell–cell reaction and in the interaction between innate and adaptive immunity. In response to an infectious stimulus, platelets will become differentially activated. Platelet activation is variable depending on whether platelets are activated by a hemostatic or pathogen stimulus. This review highlights the role that platelets play in platelet modulation count and adaptative immune response during viral infection. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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18 pages, 1405 KiB

Open AccessReview

Platelets and Their Role in Hemostasis and Thrombosis—From Physiology to Pathophysiology and Therapeutic Implications

by Alina Scridon

Int. J. Mol. Sci. 2022, 23(21), 12772; https://doi.org/10.3390/ijms232112772 - 23 Oct 2022

Cited by 20 | Viewed by 10805

Abstract

Hemostasis is a physiological process critical for survival. Meanwhile, thrombosis is amongst the leading causes of death worldwide, making antithrombotic therapy one of the most crucial aspects of modern medicine. Although antithrombotic therapy has progressed tremendously over the years, it remains far from [...] Read more.

Hemostasis is a physiological process critical for survival. Meanwhile, thrombosis is amongst the leading causes of death worldwide, making antithrombotic therapy one of the most crucial aspects of modern medicine. Although antithrombotic therapy has progressed tremendously over the years, it remains far from ideal, and this is mainly due to the incomplete understanding of the exceptionally complex structural and functional properties of platelets. However, advances in biochemistry, molecular biology, and the advent of ‘omics’ continue to provide crucial information for our understanding of the complex structure and function of platelets, their interactions with the coagulation system, and their role in hemostasis and thrombosis. In this review, we provide a comprehensive view of the complex role that platelets play in hemostasis and thrombosis, and we discuss the major clinical implications of these fundamental blood components, with a focus on hemostatic platelet-related disorders and existing and emerging antithrombotic therapies. We also emphasize a number of questions that remain to be answered, and we identify hotspots for future research. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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21 pages, 836 KiB

Open AccessReview

Oxidised Low-Density Lipoprotein-Induced Platelet Hyperactivity—Receptors and Signalling Mechanisms

by Martin Berger and Khalid M. Naseem

Int. J. Mol. Sci. 2022, 23(16), 9199; https://doi.org/10.3390/ijms23169199 - 16 Aug 2022

Cited by 10 | Viewed by 2419

Abstract

Dyslipidaemia leads to proatherogenic oxidative lipid stress that promotes vascular inflammation and thrombosis, the pathologies that underpin myocardial infarction, stroke, and deep vein thrombosis. These prothrombotic states are driven, at least in part, by platelet hyperactivity, and they are concurrent with the appearancxe [...] Read more.

Dyslipidaemia leads to proatherogenic oxidative lipid stress that promotes vascular inflammation and thrombosis, the pathologies that underpin myocardial infarction, stroke, and deep vein thrombosis. These prothrombotic states are driven, at least in part, by platelet hyperactivity, and they are concurrent with the appearancxe of oxidatively modified low-density lipoproteins (LDL) in the circulation. Modified LDL are heterogenous in nature but, in a general sense, constitute a prototype circulating transporter for a plethora of oxidised lipid epitopes that act as danger-associated molecular patterns. It is well-established that oxidatively modified LDL promote platelet activation and arterial thrombosis through a number of constitutively expressed scavenger receptors, which transduce atherogenic lipid stress to a complex array of proactivatory signalling pathways in the platelets. Stimulation of these signalling events underlie the ability of modified LDL to induce platelet activation and blunt platelet inhibitory pathways, as well as promote platelet-mediated coagulation. Accumulating evidence from patients at risk of arterial thrombosis and experimental animal models of disease suggest that oxidised LDL represents a tangible link between the dyslipidaemic environment and increased platelet activation. The aim of this review is to summarise recent advances in our understanding of the pro-thrombotic signalling events induced in platelets by modified LDL ligation, describe the contribution of individual platelet scavenger receptors, and highlight potential future challenges of targeting these pathways. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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35 pages, 996 KiB

Open AccessReview

The Role of Platelets in Diabetic Kidney Disease

by Ukhti Jamil Rustiasari and Joris J. Roelofs

Int. J. Mol. Sci. 2022, 23(15), 8270; https://doi.org/10.3390/ijms23158270 - 27 Jul 2022

Cited by 10 | Viewed by 2838

Abstract

Diabetic kidney disease (DKD) is among the most common microvascular complications in patients with diabetes, and it currently accounts for the majority of end-stage kidney disease cases worldwide. The pathogenesis of DKD is complex and multifactorial, including systemic and intra-renal inflammatory and coagulation [...] Read more.

Diabetic kidney disease (DKD) is among the most common microvascular complications in patients with diabetes, and it currently accounts for the majority of end-stage kidney disease cases worldwide. The pathogenesis of DKD is complex and multifactorial, including systemic and intra-renal inflammatory and coagulation processes. Activated platelets play a pivotal role in inflammation, coagulation, and fibrosis. Mounting evidence shows that platelets play a role in the pathogenesis and progression of DKD. The potentially beneficial effects of antiplatelet agents in preventing progression of DKD has been studied in animal models and clinical trials. This review summarizes the current knowledge on the role of platelets in DKD, including the potential therapeutic effects of antiplatelet therapies. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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Other

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9 pages, 2340 KiB

Open AccessCase Report

Pathophysiological and Molecular Basis of the Side Effects of Ticagrelor: Lessons from a Case Report

by Daniel Cesarini, Iacopo Muraca, Martina Berteotti, Anna Maria Gori, Andrea Sorrentino, Alessia Bertelli, Rossella Marcucci and Renato Valenti

Int. J. Mol. Sci. 2023, 24(13), 10844; https://doi.org/10.3390/ijms241310844 - 29 Jun 2023

Cited by 1 | Viewed by 1097

Abstract

Ticagrelor is currently considered a first-line choice in dual antiplatelet therapy (DAPT) following revascularization of acute coronary syndrome (ACS). However, its use is correlated with an increased incidence of two side effects, dyspnea and bradyarrhythmias, whose molecular mechanisms have not yet been defined [...] Read more.

Ticagrelor is currently considered a first-line choice in dual antiplatelet therapy (DAPT) following revascularization of acute coronary syndrome (ACS). However, its use is correlated with an increased incidence of two side effects, dyspnea and bradyarrhythmias, whose molecular mechanisms have not yet been defined with certainty and, consequently, neither of the therapeutic decisions they imply. We report the case of a patient with acute myocardial infarction treated with ticagrelor and aspirin as oral antithrombotic therapy after primary percutaneous coronary intervention (PCI), manifesting in a significant bradyarrhythmic episode that required a switch of antiplatelet therapy. Starting from this case report, this article aims to gather the currently available evidence regarding the molecular mechanisms underlying these side effects and propose possible decision-making algorithms regarding their management in clinical practice. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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Open AccessOpinion

Microvascular Thrombosis as a Critical Factor in Severe COVID-19

by Patricia P. Wadowski, Benjamin Panzer, Alicja Józkowicz, Christoph W. Kopp, Thomas Gremmel, Simon Panzer and Renate Koppensteiner

Int. J. Mol. Sci. 2023, 24(3), 2492; https://doi.org/10.3390/ijms24032492 - 27 Jan 2023

Cited by 10 | Viewed by 1995

Abstract

Platelet–endothelial interactions have a critical role in microcirculatory function, which maintains tissue homeostasis. The subtle equilibrium between platelets and the vessel wall is disturbed by the coronavirus disease 2019 (COVID-19), which affects all three components of Virchow’s triad (endothelial injury, stasis and a [...] Read more.

Platelet–endothelial interactions have a critical role in microcirculatory function, which maintains tissue homeostasis. The subtle equilibrium between platelets and the vessel wall is disturbed by the coronavirus disease 2019 (COVID-19), which affects all three components of Virchow’s triad (endothelial injury, stasis and a hypercoagulable state). Endotheliitis, vasculitis, glycocalyx degradation, alterations in blood flow and viscosity, neutrophil extracellular trap formation and microparticle shedding are only few pathomechanisms contributing to endothelial damage and microthrombosis resulting in capillary plugging and tissue ischemia. In the following opinion paper, we discuss major pathological processes leading to microvascular endothelial activation and thrombosis formation as a possible major adverse factor driving the deterioration of patient disease course in severe COVID-19. Full article

(This article belongs to the Special Issue Advances in Platelet Biology and Functions)

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