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Adenosine diphosphate (ADP) is the major platelet agonist, which is important in the shape changes, stability, and growth of the thrombus. Platelet activation by ADP is associated with the G protein-coupled receptors P2Y1 and P2Y12. The pharmacologic blockade of the P2Y12 receptor significantly reduces the risk of peripheral artery disease, myocardial infarction, ischemic stroke, and vascular death. Recent studies demonstrated the inhibition of ADP-induced blood platelet activation by three major compounds of the flavonolignans group: silybin, silychristin, and silydianin. For this reason, the aim of the current work was to verify the effects of silybin, silychristin, and silydianin on ADP-induced physiological platelets responses, as well as mechanisms of P2Y12-dependent intracellular signal transduction. We evaluated the effect of tested flavonolignans on ADP-induced blood platelets’ aggregation in platelet-rich plasma (PRP) (using light transmission aggregometry), adhesion to fibrinogen (using the static method), and the secretion of PF-4 (using the ELISA method). Additionally, using the double labeled flow cytometry method, we estimated platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. We demonstrated a dose-dependent reduction of blood platelets’ ability to perform ADP-induced aggregation, adhere to fibrinogen, and secrete PF-4 in samples treated with flavonolignans. Additionally, we observed that all of the tested flavonolignans were able to increase VASP phosphorylation in blood platelets samples, which is correlated with P2Y12 receptor inhibition. All of these analyses show that silychristin and silybin have the strongest inhibitory effect on blood platelet activation by ADP, while silydianin also inhibits the ADP pathway, but to a lesser extent. The results obtained in this study clearly demonstrate that silybin, silychristin, and silydianin have inhibitory properties against the P2Y12 receptor and block ADP-induced blood platelet activation. [ABSTRACT FROM AUTHOR]

Theiler's murine encephalomyelitis virus (TMEV) infection has been used as a mouse model for two virus-induced organ-specific immune-mediated diseases. TMEV-induced demyelinating disease (TMEV-IDD) in the central nervous system (CNS) is a chronic inflammatory disease with viral persistence and an animal model of multiple sclerosis (MS) in humans. TMEV infection can also cause acute myocarditis with viral replication and immune cell infiltration in the heart, leading to cardiac fibrosis. Since platelets have been reported to modulate immune responses, we aimed to determine the role of platelets in TMEV infection. In transcriptome analyses of platelets, distinct sets of immune-related genes, including major histocompatibility complex (MHC) class I, were up- or downregulated in TMEV-infected mice at different time points. We depleted platelets from TMEV-infected mice by injecting them with platelet-specific antibodies. The platelet-depleted mice had significantly fewer viral antigen-positive cells in the CNS. Platelet depletion reduced the severities of TMEV-IDD and myocarditis, although the pathology scores did not reach statistical significance. Immunologically, the platelet-depleted mice had an increase in interferon (IFN)-γ production with a higher anti-TMEV IgG2a/IgG1 ratio. Thus, platelets may play roles in TMEV infection, such as gene expression, viral clearance, and anti-viral antibody isotype responses. [ABSTRACT FROM AUTHOR]

Cardiovascular thromboembolic diseases and cancer continue to be a leading cause of death and disability worldwide. Therefore, it is crucial to advance their diagnoses and treatment in the context of individualized medicine. However, the disease specificity of the currently available markers is limited. Based on analyses of a subset of peptides and matching proteins in disease vs. healthy platelets, scientists have recently shown that focused platelet proteomics enables the quantification of disease-specific biomarkers in humans. In this review, we explored the potential of accurate platelet proteomic research, which is required to identify novel diagnostic and pharmaceutical targets by comprehending the proteome variety of healthy individuals and patients for personalized and precision medicine. [ABSTRACT FROM AUTHOR]

Avians have thrombocytes in their blood circulation rather than mammalian platelets. However, many details of thrombocyte characteristics have not been determined. Here, chicken thrombocytes were isolated, and extracellular vesicle (EV) production was investigated. The thrombocyte‐specific markers cd41 and cd61 were expressed in the yolk sac at 24 h. According to the embryonic developmental stage, the cd41‐expressing tissues changed from the yolk sac to the bone marrow and spleen. Accordingly, the bone marrow and spleen were the main tissues producing thrombocytes in adult chickens. Avian thrombocytes were separated from adult spleen cells through a combination of discontinuous density gradient centrifugation, phagocytic cell removal, and fluorescence‐activated cell sorting. Isolated thrombocytes produced CD41+ EVs (CD41+ EVs), and the CD41+ EVs also expressed CD9. Microarray analysis revealed that CD41+ EVs contain many microRNAs. Macrophage lines (RAW264.7) phagocytosed CD41+ EVs, and their phagocytosis and migration activity were suppressed. Microarray analysis also revealed that EVs altered gene expression in macrophages. These data indicated that the CD41+ EV was a carrier of microRNAs produced from thrombocytes and affected the cell characteristics of the received cells. Therefore, the CD41+ EVs of avians worked as a communication tool. [ABSTRACT FROM AUTHOR]

Previous studies have shown that human platelets and megakaryocytes carry microRNAs suggesting their role in platelet function and megakaryocyte development, respectively. However, a comprehensive study on the microRNAs and their targets has not been undertaken. Zebrafish thrombocytes could be used as a model to study their role in megakaryocyte maturation and platelet function because thrombocytes have both megakaryocyte features and platelet properties. In our laboratory, we identified 15 microRNAs in thrombocytes using single-cell RNA sequencing. We knocked down each of these 15 microRNAs by the piggyback method and found knockdown of three microRNAs, mir-7148, let-7b, and mir-223 in adult zebrafish led to an increase in the percentage of thrombocytes. Functional thrombocyte analysis using plate tilt assay showed no modulatory effect of the three microRNAs on thrombocyte aggregation/agglutination. We also found enhanced thrombosis using arterial laser thrombosis assay in a group of zebrafish larvae after mir-7148, let-7b, and mir-223 knockdowns. These results suggested mir-7148, let-7b, and mir-223 are repressors for thrombocyte production. We then explored miRWalk database for let-7b downstream targets and then selected those that are expressed in thrombocytes, and from this list based on their role in differentiation selected 14 genes, rorca, tgif1, rfx1a, deaf1, zbtb18, mafba, cebpa, spi1a, spi1b, fhl3b, ikzf1, irf5, irf8, and lbx1b that encode transcriptional regulators. The qRT-PCR analysis of expression levels of the above genes following let-7b knockdown showed changes in the expression of 13 targets. We then studied the effect of the 13 targets on thrombocyte production and identified 5 genes, irf5, tgif1, irf8, cebpa, and rorca that showed thrombocytosis and one gene, ikzf1 that showed thrombocytopenia. Furthermore, we tested whether mir-223 regulates any of the above 13 transcription factors after mir-223 knockdown using qRT-PCR. Six of the 13 genes showed similar gene expression as observed with let-7b knockdown and 7 genes showed opposing results. Thus, our results suggested a possible regulatory network in common with both let-7b and mir-223. We also identified that tgif1, cebpa, ikzf1, irf5, irf8, and ikzf1 play a role in thrombopoiesis. Since the ikzf1 gene showed a differential expression profile in let-7b and mir-223 knockdowns but resulted in thrombocytopenia in ikzf1 knockdown in both adults and larvae we also studied an ikzf1 mutant and showed the mutant had thrombocytopenia. Taken together, these studies showed that thrombopoiesis is controlled by a network of transcription regulators that are regulated by multiple microRNAs in both positive and negative manner resulting in overall inhibition of thrombopoiesis. [ABSTRACT FROM AUTHOR]

Dysfunction of the immune response is regarded as a prominent feature of neurological diseases, including neurodegenerative diseases, malignant tumors, acute neurotraumatic insult, and cerebral ischemic/hemorrhagic diseases. Platelets play a fundamental role in normal hemostasis and thrombosis. Beyond those normal functions, platelets are hyperactivated and contribute crucially to inflammation and immune responses in the central nervous system (CNS). Mitochondria are pivotal organelles in platelets and are responsible for generating most of the ATP that is used for platelet activation and aggregation (clumping). Notably, platelet mitochondria show marked morphological and functional alterations under heightened inflammatory/oxidative stimulation. Mitochondrial dysfunction not only leads to platelet damage and apoptosis but also further aggravates immune responses. Improving mitochondrial function is hopefully an effective strategy for treating neurological diseases. In this review, the authors discuss the immunomodulatory roles of platelet-derived mitochondria (PLT-mitos) in neurological diseases and summarize the neuroprotective effects of platelet mitochondria transplantation. [ABSTRACT FROM AUTHOR]

Background: Arachidonic acid metabolism by cyclooxygenase (COX) is a major pathway for blood platelets' activation, which is associated with pro-thrombotic platelet activity and the production of pro-inflammatory mediators. Inhibition of COX activity is one of the major means of anti-platelet pharmacotherapy preventing arterial thrombosis and reducing the incidence of cardiovascular events. Recent studies have presented that a silymarin (standardized extract of Milk thistle (Silybum marianum)) can inhibit the COX pathway. Accordingly, the aim of our study was to determine the effects of three major flavonolignans (silybin, silychristin and silydianin) on COX pathway activity in blood platelets. Methods: We determined the effect of flavonolignans on arachidonic acid induced blood platelet aggregation, COX pathway metabolites formation, as well as COX activity in platelets. Additionally, we analysed the potential mechanism of this interaction using the bioinformatic ligand docking method. Results: We observed that tested compounds decrease the platelet aggregation level, both thromboxane A2 and malondialdehyde formation, as well as inhibit the COX activity. The strongest effect was observed for silychristin and silybin. In our in silico study we showed that silychristin and silybin have conformations which interact with the active COX site as competitive inhibitors, blocking the possibility of substrate binding. Conclusions: The results obtained from this study clearly present the potential of flavonolignans as novel antiplatelet and anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

It is currently believed that plaque complication, with the consequent superimposed thrombosis, is a key factor in the clinical occurrence of acute coronary syndromes (ACSs). Platelets are major players in this process. Despite the considerable progress made by the new antithrombotic strategies (P2Y12 receptor inhibitors, new oral anticoagulants, thrombin direct inhibitors, etc.) in terms of a reduction in major cardiovascular events, a significant number of patients with previous ACSs treated with these drugs continue to experience events, indicating that the mechanisms of platelet remain largely unknown. In the last decade, our knowledge of platelet pathophysiology has improved. It has been reported that, in response to physiological and pathological stimuli, platelet activation is accompanied by de novo protein synthesis, through a rapid and particularly well-regulated translation of resident mRNAs of megakaryocytic derivation. Although the platelets are anucleate, they indeed contain an important fraction of mRNAs that can be quickly used for protein synthesis following their activation. A better understanding of the pathophysiology of platelet activation and the interaction with the main cellular components of the vascular wall will open up new perspectives in the treatment of the majority of thrombotic disorders, such as ACSs, stroke, and peripheral artery diseases before and after the acute event. In the present review, we will discuss the novel role of noncoding RNAs in modulating platelet function, highlighting the possible implications in activation and aggregation. [ABSTRACT FROM AUTHOR]

Introduction: Despite therapy, patients operated using a cardiopulmonary bypass demonstrate increased platelet aggregation, which rebounds to above preoperative levels. The aim of the study was to test the interaction between platelet reactivity/activation and selected inflammatory markers in the post-operative period. Material and methods: In total, 103 patients with non-ST elevation acute coronary syndrome (NSTE-ACS) who were not eligible for percutaneous coronary interventions (PCI), and required urgent revascularization, were included. Platelet reactivity was measured using the PFA-100 platelet analyser, multiple electrode aggregometry, and was expressed as a novel platelet reactivity score (PRS). Patients were divided using their PRS scores into high platelet relativity or low platelet reactivity subgroups (HPR or LPR). Platelet basal activation was measured using immunoassays for soluble P-selectin and soluble CD40L. We measured high-sensitivity C-reactive protein (CRP), and used immunoassays for tumour necrosis factor α (TNF-α) and interleukin 6 (IL-6) as inflammation markers. Results: Significant differences between HPR and LPR groups were found for CRP (mg/l): 81.5 vs. 44.6, p < 0.02; and TNF-α (pg/l): 3.51 vs. 2.37, p < 0.02. A significant association was found between CRP, TNF-α, IL-6 and platelet reactivity (platelet reactivity score). Cohen's k showed: CRP = 0.49, p < 0.0001, TNF-α = 0.37, p < 0.002. Perioperative myocardial infarction and rhythm disturbances occurred more frequently in the high platelet reactivity group: 7 (16.3%) vs. 2 (3.3%), p < 0.04, and 9 (20.9%) vs. 4 (6.7%), p < 0.04, respectively. Conclusions: Inflammatory parameters CRP and TNF-α are strongly associated with platelet reactivity (expressed as PRS) in cardiopulmonary bypass graft patients. Platelet hyperreactivity in the early post-operative period combined with a systemic inflammatory state correlates with a higher risk of post-operative rhythm disturbances and myocardial infarction. [ABSTRACT FROM AUTHOR]

Background: The HALP score (hemoglobin, albumin, lymphocyte, and platelet) is a novel indicator that measures systemic inflammation and nutritional status. The goal of this study was to look into the relationship between the HALP score and post-stroke cognitive impairment (PSCI) in people who had an acute ischemic stroke (AIS). Methods: A total of 592 individuals with ischemic stroke were included in the research, and the PSCI (n = 382) and non-PSCI (n = 210) groups were determined using the Mini-Mental State Examination scale 2 weeks following the stroke. HALP score was computed by the formula: hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L) / platelets (/L), and was split into three layers according to the tertiles. The connection between the HALP and cognitive results was investigated by binary logistic regression. Results: The PSCI group's HALP score was much lower than the non-PSCI group's (p < 0.001). The HALP score was divided into three layers: T1 ≤ 34.0, T2 34.1–49.4, and T3 ≥ 49.5, respectively. In the binary regression analysis, taking the T3 layer as the reference, the T1 layer showed the highest risk of PSCI after adjusting for confounding factors (odds ratio (OR) = 1.965, 95% confidence interval (CI) = 1.237–3.122, p = 0.004), while there was no increased risk of PSCI in the T2 layer (OR = 1.538, 95%CI = 0.983–2.404, p = 0.059). Conclusion: Low HALP score at admission was found to be correlated with early-onset PSCI and may help clinicians in the early identification of high-risk patients. [ABSTRACT FROM AUTHOR]

Recently, long noncoding RNAs (lncRNAs) have been key regulators for both mRNAs and proteins in nucleated cells. However, the expression profiles of lncRNAs in non-nucleated cells such as platelets are currently unclear. In this study, we determined the expression profiles of lncRNAs in human platelets. We found that 6109 lncRNAs were expressed in human platelets. Interestingly, 338 lncRNAs were differentially expressed in hyperreactive and hyporeactive platelets. Bioinformatics' analysis revealed that these aberrantly expressed lncRNAs might be related to platelet activity and other platelet functions. To provide a proof of concept, we measured the expression levels of PARLncRNA-1, a down-regulated lncRNA of hyperreactive platelets, in platelets from 12 patients with acute myocardial infarction and their controls. We found that the lncRNA was also significantly down-regulated in platelets from patients, which was partially reversed by treatment with aspirin a known antiplatelet drug. LncRNAs may represent a novel class of modulators for platelet functions. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute Coronary Syndrome is a disease of the circulatory system characterized by the partial or complete blockage of coronary arteries. In thrombosis, a major role is played by platelets—the smallest, anucleate, morphotic elements in the bloodstream. Platelets are involved in the process of hemostasis, which ensures the continuity of the blood vessel by forming a clot that prevents blood loss. Unique structures of blood platelets ensure their high reactivity in the vascular microenvironment due to the interaction with many biologically active molecules, which is recognized by the surface receptors. The research carried out in the manuscript is aimed at detecting potential changes at the molecular level in platelet surface receptors that could constitute the potential importance of the occurrence of Acute Coronary Syndrome. The obtained results indicate that the P2Y12 receptor, which is the main target of antiplatelet therapy, is expressed more frequently among patients. In addition, we have shown that at the genetic level, quantitative changes also occur in the case of other receptors that are important in the activation of platelets. The following manuscript suggests the potential mechanisms responsible for the differences between patients and healthy donors due to a better understanding of the molecular causes of Acute Coronary Syndrome pathogenesis. The pathological conditions caused by blood platelet activation constitute a fundamental core in the pathogenesis of Acute Coronary Syndrome (ACS). The hyperactivity of platelets in ACS is well-documented, but there is still little research into the molecular basis of phenotypic changes in platelet functionality. To expand the knowledge of this phenomenon, we analyzed the disturbances in the expression of several key platelet receptors and the aspect of regulating potential abnormalities. Platelet surface receptors are responsible for maintaining the hemostatic balance, platelet interaction with immune cells, and support of the coagulation cascade leading to occlusion of the vessel lumen. Due to their prominent role, platelet receptors constitute a major target in pharmacological treatment. Our work aimed to identify the molecular alteration of platelet surface receptors, which showed augmented mRNA expression of P2Y12, GP1BB, ITGA2B, and ITGB3 and increased protein concentrations of P2Y12 and GP IIb/IIIa in ACS. The upregulation of the P2Y12 level was also confirmed by confocal and cytometric visualization. Furthermore, we evaluated the expression of two microRNAs: miR-223-3p and miR-126-3p, which were suggested to regulate platelet P2Y12 expression. Results of our study present new insight into the molecular background of ACS. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) is highly vascularized where neuronal cells are located in proximity to endothelial cells, astroglial limitans, and neuronal processes constituting integrated neurovascular units. In contrast to many other organs, the CNS has a blood-brain barrier (BBB), which becomes compromised due to infection, neuroinflammation, neurodegeneration, traumatic brain injury, and other reasons. BBB disruption is presumably involved in neuronal injury during epilepsy and psychiatric disorders. Therefore, many types of neuropsychological disorders are accompanied by an increase in BBB permeability leading to direct contact of circulating blood cells in the capillaries with neuronal cells in the CNS. The second most abundant type of blood cells are platelets, which come after erythrocytes and outnumber ~100-fold circulating leukocytes. When BBB becomes compromised, platelets swiftly respond to the vascular injury and become engaged in thrombosis and hemostasis. However, more recent studies demonstrated that platelets could also enter CNS parenchyma and directly interact with neuronal cells. Within CNS, platelets become activated by recognizing major brain gangliosides on the surface of astrocytes and neurons and releasing a milieu of pro-inflammatory mediators, neurotrophic factors, and neurotransmitters. Platelet-derived factors directly stimulate neuronal electric and synaptic activity and promote the formation of new synapses and axonal regrowth near the site of damage. Despite such active involvement in response to CNS damage, the role of platelets in neurological disorders was not extensively studied, which will be the focus of this review. [ABSTRACT FROM AUTHOR]

Differentiating the aetiology of thrombocytosis is limited yet crucial in patients with essential thrombocythaemia (ET). MicroRNAs (miRNAs) regulate haematopoiesis and lineage commitment; aberrant expression of miRNAs plays an important role in myeloproliferative neoplasms. However, the miRNA profile has been poorly explored in ET patients compared to patients with reactive thrombocytosis (RT). A total of 9 samples, including 5 ET patient samples, 2 RT patient samples, and 2 healthy control samples, were analysed in this study. We produced 81.43 million reads from transcripts and 59.60 million reads from small RNAs. We generated a comprehensive miRNA-mRNA regulatory network and identified unique 14 miRNA expression patterns associated with ET. Among the 14 miRNAs, miR-1268a was downregulated in ET and showed an inverse correlation with its 8 putative target genes, including genes associated with thrombus formation and platelet activation (CDH6, EHD2, FUT1, KIF26A, LINC00346, PTPRN, SERF1A, and SLC6A9). Principal component analysis (PCA) showed ET and non-ET groups well clustered in space, suggesting each group had a distinctive expression pattern of mRNAs and miRNAs. These results suggest that the significant dysregulation of miR-1268a and its 8 target genes could be a unique expression of platelet mi-RNAs and miRNA/mRNA regulatory network in ET patients. [ABSTRACT FROM AUTHOR]

The authors conclude that regenerative medicine application, based on administration of platelet-derived products, should take into account that plasma is necessary for platelet protein activity. Zhao and Devine [[1]] exhaustively provide an update on in vitro storage characteristics and in vivo transfusion effects of cold-stored platelets. What emerges is that platelet proteomics can be useful in addressing basic research questions, as well as in improving platelet transfusion medicine and therapeutic management of platelet dysfunction. [Extracted from the article]

Platelets are clearly central to thrombosis and hemostasis. In addition, more recently, evidence has emerged for non-hemostatic roles of platelets including inflammatory and immune reactions/responses. Platelets express immunologically relevant ligands and receptors, demonstrate adhesive interactions with endothelial cells, monocytes and neutrophils, and toll-like receptor (TLR) mediated responses. These properties make platelets central to innate and adaptive immunity and potential candidate key mediators of autoimmune disorders. Multiple sclerosis (MS) is the most common chronic autoimmune central nervous system (CNS) disease. An association between platelets and MS was first indicated by the increased adhesion of platelets to endothelial cells. This was followed by reports identifying structural and functional changes of platelets, their chronic activation in the peripheral blood of MS patients, platelet presence in MS lesions and the more recent revelation that these structural and functional abnormalities are associated with all MS forms and stages. Investigations based on the murine experimental autoimmune encephalomyelitis (EAE) MS model first revealed a contribution to EAE pathogenesis by exacerbation of CNS inflammation and an early role for platelets in EAE development via platelet-neuron and platelet-astrocyte associations, through sialated gangliosides in lipid rafts. Our own studies refined and extended these findings by identifying the critical timing of platelet accumulation in pre-clinical EAE and establishing an initiating and central rather than merely exacerbating role for platelets in disease development. Furthermore, we demonstrated platelet-neuron associations in EAE, coincident with behavioral changes, but preceding the earliest detectable autoreactive T cell accumulation. In combination, these findings establish a new paradigm by asserting that platelets play a neurodegenerative as well as a neuroinflammatory role in MS and therefore, that these two pathological processes are causally linked. This review will discuss the implications of these findings for our understanding of MS, for future applications for imaging toward early detection of MS, and for novel strategies for platelet-targeted treatment of MS. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is an immune-mediated inflammatory skin disease in conjunction with the systemic inflammatory process. It appears to be related to increased risks of cardiovascular disease events, especially in severe cases. The hemostatic balance is disrupted due to the prothrombotic bias in psoriasis, which might be mainly preserved by platelet hyperactivity. Platelets are also immune cells that initiate and regulate immune and inflammatory processes, except as the principal mediator of hemostasis and thrombosis, and platelet dysfunction is deeply involved in the pathogenesis of psoriasis. Summary: The aim of this study is to perform a review that expounds abnormal platelet function in psoriasis and explains the important role of platelets in the pathogenic mechanism of psoriasis in order to provide new targets for comprehensive medical treatment. [ABSTRACT FROM AUTHOR]

Background: The microparticle content (MP%) of apheresis platelets-a marker of platelet activation-is influenced by donor factors and by external stressors during collection and storage. This study assessed the impact of apheresis technology and other factors on the activation status (MP%) of single-donor apheresis platelets.Study Design and Methods: Data from six US hospitals that screened platelets by measuring MP% through dynamic light scattering (ThromboLUX) were retrospectively analyzed. Relative risks (RRs) were derived from univariate and multivariable regression models, with activation rate (MP% ≥15% for plasma-stored platelets; ≥10% for platelet additive solution [PAS]-stored platelets) and MP% as outcomes. Apheresis platform (Trima Accel vs Amicus), storage medium (plasma vs PAS), pathogen reduction, storage time, and testing location were used as predictors.Results: Data were obtained from 7511 platelet units collected using Trima (from 16 suppliers, all stored in plasma, 20.0% were pathogen-reduced) and 2456 collected using Amicus (from four different collection facilities of one supplier, 65.0% plasma-stored, 35.0% PAS-stored, none pathogen-reduced). Overall, 30.0% of Trima platelets were activated compared to 45.6% of Amicus platelets (P < .0001). Multivariable analysis identified apheresis platform as significantly associated with platelet activation, with a lower activation rate for Trima than Amicus (RR: 0.641, 95% confidence interval [CI]: 0.578; 0.711, P < .0001) and a 6.901% (95% CI: 5.926; 7.876, P < .0001) absolute reduction in MP%, when adjusting for the other variables.Conclusion: Trima-collected platelets were significantly less likely to be activated than Amicus-collected platelets, irrespective of the storage medium, the use of pathogen reduction, storage time, and testing site. [ABSTRACT FROM AUTHOR]

Background: In multiple sclerosis (MS), clinical assessment, MRI and cerebrospinal fluid are important in the diagnostic process. However, no blood biomarker has been confirmed as a useful tool in the diagnostic work-up. Objectives: Blood platelets contain a rich spliced mRNA repertoire that can alter during megakaryocyte development but also during platelet formation and platelet circulation. In this proof of concept study, we evaluate the diagnostic potential of spliced blood platelet RNA for the detection of MS. Methods: We isolated and sequenced platelet RNA of blood samples obtained from 57 MS patients and 66 age- and gender-matched healthy controls (HCs). 60% was used to develop a particle swarm-optimized (PSO) support vector machine classification algorithm. The remaining 40% served as an independent validation series. Results: In total, 1249 RNAs with differential spliced junction expression levels were identified between platelets of MS patients as compared to HCs, including EPSTI1, IFI6, and RPS6KA3, in line with reported inflammatory signatures in the blood of MS patients. The RNAs were subsequently used as input for a MS classifier, capable of detecting MS with 80% accuracy in the independent validation series. Conclusions: Spliced platelet RNA may enable the blood-based diagnosis of MS, warranting large-scale validation. [ABSTRACT FROM AUTHOR]

Background: Although several previous studies have examined the association between the platelet to lymphocyte ratio (PLR) and acute appendicitis (AA), findings have been controversial. We aimed to systematically assess the available evidence to elucidate the overall relationship between the PLR and AA. Methods: Pubmed and Embase databases were searched for all available published literature before August, 2019 by two independent investigators for observational studies reporting the association between the PLR and AA. Random effects models were applied for all meta-analyses. Pooled standardized mean difference (SMD) and 95% confidence interval (CI) were calculated as effect estimates. Results: Eleven articles met the inclusion criteria and included in this study. Meta-analysis showed that the level of PLR in the AA group was significantly higher than that in the control group (SMD: 1.19, 95% CI: 0.75 to 1.62, P<0.001). A series of subgroup analyses were conducted to investigate the heterogeneity, showing a significant increase in PLV levels in adults with age ≥30 years (SMD: 1.46, 95% CI: 0.89 to 2.02),compared to those in adult <30 years(SMD: 0.58, 95% CI: 0.12 to 1.04) or in children (SMD: 1.03, 95% CI: 0.51 to 1.56). Compared to non-AA controls, a significant increased PLR level was also observed in non-perforated AA (SMD: 1.23, 95% CI: 0.88 to 1.59) and in AA patients during pregnancy (SMD: 0.70, 95% CI: 0.36 to 1.04), while not in perforated AA (SMD: 2.28, 95% CI: -1.72 to 6.28). Conclusions: A significant increase in PLR level is found in patients with AA, indicating that PLR is a promising biomarker for AA. PLR provides a convenient option for emergency department to quickly screen for clinically or radiologically confirmed AA awaiting appendectomy, especially for pregnant women suspected of having AA. More high-quality evidence is needed to further confirm the diagnostic accuracy of PLR for AA. [ABSTRACT FROM AUTHOR]

Epidemiological studies indicate a high risk of stroke, heart failure and myocardial infarction in patients with multiple sclerosis, especially in its secondary progressive (SPMS) phase. Some ischaemic events are directly associated with abnormal platelet functions and their prothrombotic activity. Recent reports, including this study, confirm the increased activation of circulating platelets in SPMS, and also show increased platelet reactivity, among other responses, as well as strong aggregation. In this current study, we conducted a comparative analysis of the platelet proteome in SPMS patients and in healthy controls, to demonstrate the quantitative and qualitative differences likely to affect functional changes observed in SPMS. During densitometry evaluation of 2‐D fluorescence difference gel electrophoresis, we observed differences between the electrophoretic patterns of SPMS platelets and the control samples. To determine a detailed characterisation of the proteome changes in the SPMS patients' blood platelets, in the next stage, we performed mass spectrometry of selected spots and indicated the increased presence of four proteins (fibrinogen, α‐2 macroglobulin, septin‐14 and tubulin β‐1 chain). The most important of these is the increased amount of prothrombotic protein, fibrinogen, which seems to confirm the accuracy of the imaging and potentially explains the increased risk of platelet‐origin thrombotic events. This study provides new knowledge of the potential existence of the molecular mechanisms responsible for the acceleration of the platelet pro‐coagulant function in SPMS. This can help to identify new targets for therapy, which can then be used not only in the second stage of the disease. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are an increasing problem in the modern world. Multiple sclerosis (MS) is a major human demyelinating and degenerative disease of the central nervous system (CNS). There are many reports that point to the significant role of platelet--leukocyte interaction in neurodegenerative diseases and cardiovascular disturbances. Epidemiological studies confirm the high risk of cardiovascular diseases in patients with MS. The pathophysiology mechanisms of this multi-component disease are very complex and involve various types of cells. There is increasing evidence that some co-stimulatory pathways affect the function of inflammatory cells, both in the periphery and in the CNS. Interactions of leukocytes and endothelial cells (ECs) could be significantly modulated in the presence of activated blood platelets. The supposed role of activated platelets in the development of vessel inflammatory response is due to their ability to adhere to inflamed ECs or proteins included in the subendothelial layer of the blood vessel wall, as well as to the ability of platelets to form aggregates with leukocytes. Blood platelets are able to directly activate leukocytes through a receptor-dependent mechanism or, indirectly, by biologically active compounds secreted from their granules. Cell--cell interactions provide critical mechanisms by which platelets link thrombosis, inflammation and related processes, such as diapedesis and leukocyte infiltration, to the affected vessel. Determining the relationship between platelet--leukocyte interactions and the development of neuroinflammation in the course of MS may provide new therapeutic targets in the future. [ABSTRACT FROM AUTHOR]

The blood platelets are multifunctional blood cells which are involved in the initiation of atheroma, endothelial dysfunction, and modulation of inflammatory and immune responses in the pathophysiology of many diseases. Because of their multifaceted pro‐inflammatory activity, platelets may be involved in the pathogenesis of autoimmune thyroid diseases (AITDs), such as Hashimoto's thyroiditis and Graves' disease. The aim of this study was to assess the level of activation and response ability of platelets in AITDs. We used the flow cytometry technique and kinetic measurement of aggregation to analyse platelet function immediately after blood collection and to demonstrate their activation in the circulation of patients with AITDs. We noted reorganization of platelet subpopulations (normal platelets, microparticles and aggregates) in AITDs, dependent on the degree of cell activation. We proved the elevated expression of the active form of integrin receptor GPIIb/IIIa, responsible for platelet aggregation, and in the kinetic test we confirmed the increased aggregation of platelets in different intracellular signal pathways (dependent on ADP, collagen, arachidonic acid). Our study demonstrates the high platelet activation level found in AITDs. [ABSTRACT FROM AUTHOR]

Platelets play an important role in vascular homeostasis through their interaction with circulating blood cells as well as the vascular wall. Platelet-mediated communication with other cells can take the form of direct cell-cell interactions via membrane receptors or indirectly through the release of different soluble factors stored in their granules as well as through the release of microparticles. The latter carry different proteins and RNAs which are transferred to the target cells. The aim of this review is to discuss the role of platelet-derived factors, adhesion molecules as well as RNAs as mediators of the cross-talk between platelets and the vessel wall. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The study covers an evaluation of the influence of extracts (1–50 μg/ml), isolated from aerial parts of nine Trifolium L. species (i.e. T. alexandrinum, T. fragiferum, T. hybridum, T. incarnatum, T. pallidum, T. pratense, T. resupinatum var. majus, T. resupinatum var. resupinatum and T. scabrum) on haemostatic properties of blood plasma. Methods: The clot formation and fibrinolysis assay (CFF), blood clotting times, the extrinsic and intrinsic coagulation pathway‐dependent polymerization of plasma fibrin were measured. The effects of plant extracts on amidolytic activity of thrombin were also evaluated and compared with argatroban, an antithrombotic drug. Cytotoxicity was assessed in a model of blood platelets and as the viability of peripheral blood mononuclear cells. Key findings: While no changes in blood clotting times or fibrinolytic properties of blood plasma were found, some fractions impaired the blood plasma coagulation induced by the intrinsic coagulation pathway. Reduction in the maximal velocity of fibrin polymerization was also observed in the clot formation and fibrinolysis assay. No cytotoxicity of Trifolium extracts towards the investigated cells was recorded. Conclusions: The most efficient anticoagulant activity in plasma was found for T. fragiferum and T. incarnatum extracts, while the T. alexandrinum fraction was the most effective inhibitor of thrombin amidolytic activity. [ABSTRACT FROM AUTHOR]

Copyright of Postepy Psychiatrii i Neurologii / Advances in Psychiatry & Neurology is the property of Termedia Publishing House and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The epidemiological studies confirm an increased risk of cardiovascular disease in multiple sclerosis, especially prothrombotic events directly associated with abnormal platelet activity. The aim of our study was to investigate the level of blood platelet activation in the circulation of patients with chronic phase of multiple sclerosis (SP MS) and their reactivity in response to typical platelets' physiological agonists. We examined 85 SP MS patients diagnosed according to the revised McDonald's criteria and 50 healthy volunteers as a control group. The platelet activation and reactivity were assessed using flow cytometry analysis of the following: P-selectin expression (CD62P), activation of GP IIb/IIIa complex (PAC-1 binding), and formation of platelet microparticles (PMPs) and platelet aggregates (PA) in agonist-stimulated (ADP, collagen) and unstimulated whole blood samples. Furthermore, we measured the level of soluble P-selectin (sP-selectin) in plasma using ELISA method, to evaluate the in vivo level of platelet activation, both in healthy and SP MS subjects. We found a statistically significant increase in P-selectin expression, GP IIb/IIIa activation, and formation of PMPs and PA, as well as in unstimulated and agonist-stimulated (ADP, collagen) platelets in whole blood samples from patients with SP MS in comparison to the control group. We also determined the higher sP-selectin level in plasma of SP MS subjects than in the control group. Based on the obtained results, we might conclude that during the course of SP MS platelets are chronically activated and display hyperreactivity to physiological agonists, such as ADP or collagen. [ABSTRACT FROM AUTHOR]

Context:The main source of bufadienolides is toad venom; however, plants such as members ofKalanchoeAdans. (Crassulaceae) genus may also synthesize these bioactive substances. Objective:This is the first study on antioxidant effects and cytotoxicity of bufadienolide-rich fraction isolated fromKalanchoe daigremontianaRaym.-Hamet & H. Perrier. Materials and methods:The methanolic fraction was extracted from the plant roots and contained 0.48 mg bufadienolides/mg of dry mass (11α,19-dihydroksytelocinobufagin, bersaldegenin-1-acetate, bersaldegenin-1,3,5-orthoacetate, 19-(acetyloxy)-3β,5β,11α,14-tetrahydroxyl-12-oxo-bufa-20,22-dienolide and 19-(acetyloxy)-1β,3β,5β,14-tetrahydroxyl-bufa-20,22-dienolide, mainly). The cytotoxicity ofK. daigremontianafraction was evaluated in anin vitroexperimental model of blood platelets. The viability of blood platelets was determined on the basis of a release of lactate dehydrogenase. Results:The fraction scavenged DPPH•radicals, with EC50of 21.80 μg/mL. Studies on an experimental model of blood plasma under peroxynitrite-induced oxidative stress revealed that the plant preparation had moderate antioxidant properties. Levels of 3-nitrotyrosine and thiol groups indicated that the protective effect ofK. daigremontianawas significant mainly for its concentration of 50 μg/mL. No effect was found in prevention of oxidation of low-molecular plasma thiols (glutathione, cysteine and cysteinylglycine). Simultaneously, measurements of lipid hydroperoxides and thiobarbituric acid-reactive substances (TBARS) indicated that the examined fraction might be effective antioxidant at broader concentration range, that is 1–5 and 25–50 μg/mL for hydroperoxides and TBARS generation, respectively. No cytotoxicity was observed at the concentration range of 1–50 μg/mL. Conclusions:Based on the obtained results, we suggest that antioxidant activity may additionally contribute to beneficial properties ofK. daigremontiana-derived extracts. [ABSTRACT FROM AUTHOR]

Platelet activation is increasingly postulated as a possible component of the pathogenesis of multiple sclerosis (MS), especially due to the increased risk of cardiovascular events in MS. Arachidonic acid cascade metabolized by cyclooxygenase (COX) is a key pathway of platelet activation. The aim of our study was to investigate the COX-dependent arachidonic acid metabolic pathway in blood platelets from secondary progressive multiple sclerosis (SP MS) patients. The blood samples were obtained from 50 patients (man n = 22; female n = 28), suffering from SP MS, diagnosed according to the revised McDonald criteria. Platelet aggregation was measured in platelet-rich plasma after arachidonic acid stimulation. The level of COX activity and thromboxane B concentration were determined by ELISA method. Lipid peroxidation was assessed by measuring the level of malondialdehyde. The results were compared with a control group of healthy volunteers. We found that blood platelets obtained from SP MS patients were more sensitive to arachidonic acid and their response measured as platelet aggregation was stronger (about 14 %) relative to control. We also observed a significantly increased activity of COX (about 40 %) and synthesis of thromboxane B (about 113 %). The generation of malondialdehyde as a marker of lipid peroxidation was about 10 % higher in SP MS than in control. Cyclooxygenase-dependent arachidonic acid metabolism is significantly increased in blood platelets of patients with SP MS. Future clinical studies are required to recommend the use of low-dose aspirin, and possibly other COX inhibitors in the prevention of cardiovascular risk in MS. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease. It is a group of chronic disorders characterized by inflammation of the gastrointestinal track with unknown etiology. Currently applied biomarkers include CRP, ESR, pANCA, ASCA, and fecal calprotectin. The etiopathogenesis of IBD is multifactorial. In patients with IBD in inflamed alimentary tract mucosa the number of recruited monocytes and activated macrophages which are source of cytokines. In IBD, the exacerbation is accompanied by thrombocytosis. Platelets play a crucial role in the hemostasis and inflammatory response. Selectins, which regulates the hemostasis and inflammatory response, stimulates the secretion of many inflammatory mediators such as β-thromboglobuline, CD40L, fibrinogen, IL-1β, platelet factor-4. In the course of IBD the following changes are observed: an increase in the number of platelets (reactive thrombocytosis), PDW and PCT, reduction in MPV, increased production and excretion of granular content products (P-selectin, GP53, β-TG, PF-4, vWF, fibrinolytic inhibitors). [ABSTRACT FROM AUTHOR]

A growing number of reports indicate that some species of clover ( Trifolium) may have remarkable medical importance; however, the effects of these plants on blood platelets and hemostasis are inadequately recognized. This work was designed to study the effects of Trifolium pallidum and Trifolium scabrum extracts on the functions of human blood platelets in vitro. Platelet suspensions were preincubated with extracts from aerial parts of T. pallidum (phenolic fraction and clovamide fraction) and T. scabrum (phenolic fraction) at the final concentrations of 12.5, 25, and 50 µg/ml. Then, for platelet activation thrombin (0.1 U/ml), thrombin receptor activating peptide (TRAP; 20 µM), or adenosine diphosphate (ADP; 1 µM) were used. The effects of Trifolium extracts on adhesion of blood platelets to fibrinogen and collagen were determined by enzyme-linked immunosorbent assay (ELISA) method. Platelet aggregation was monitored on a dual-channel Chronolog aggregometer. In these studies, we also compared the action of tested plant extracts with the effects of another antiplatelet plant-derived compound - resveratrol (3,4′,5-trihydroxystilbene). The performed assays demonstrated that the tested extracts might influence the platelet functions in vitro. The inhibitory, concentration-dependent effects of all tested extracts on adhesion of thrombin-stimulated platelets to collagen was found. Both extracts from T. pallidum and from T. scabrum reduced the thrombin-induced platelet adhesion to fibrinogen. Furthermore, in the presence of all three extracts, the platelet aggregation induced by thrombin was slightly inhibited. Our results also indicate that the tested plant extracts (at the highest concentrations used of 50 µg/ml), similar to purified resveratrol, inhibit selected steps of platelet activation stimulated by both proteolytic (thrombin) and nonproteolytic agonists (TRAP or ADP). In the comparative studies, T. pallidum and T. scabrum extracts was not found to be more effective antiaggregatory factor, than resveratrol. Extracts from T. pallidum and T. scabrum aerial parts reveal antiplatelet properties: the antiadhesive effect was similar to that of the reference compound resveratrol, whereas the antiaggregant effect was less marked. The results obtained suggest that these plants may be a promising source of natural compounds, valuable in the prevention of the enhanced activity of blood platelets in numerous cardiovascular diseases, observed in menopausal or postmenopausal women. [ABSTRACT FROM AUTHOR]

Copyright of Advances in Hygiene & Experimental Medicine / Postepy Higieny i Medycyny Doswiadczalnej is the property of Sciendo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Mechanisms involved in the reduction of blood platelet functions by various plant extract, including the grape seeds extract (rich in phenolic compounds, a mixture of about 95% oligomeric phenols; GSE) are still unclear. In the literature there are few papers describing studies on the effects of GSE on selected element of hemostasis. The aim of our study was to establish and compare the influence of GSE (at final dose of 0.625-50 µg/ml) and resveratrol (3,4′,5 - trihydroxystilben), a phenolic compound synthesized in grapes and vegetables and presents in wine, which has been supposed to be beneficial for the prevention of cardiovascular events, on different steps of platelet activation. We measured the effects of GSE and resveratrol on platelet aggregation, the surface expression of P-selectin, platelet microparticle formation (PMP), and superoxide anion radicals () production in blood platelets stimulated by TRAP and thrombin. P-selectin expression and PMP formation were measured by a flow cytometer. In gel-filtered platelets activated by thrombin or TRAP and treated with different concentrations of GSE (1.25-50 µg/ml) a significant decrease of P-selectin expression, PMP formation and platelet aggregation was observed. GSE caused also a dose-dependent reduction of produced in platelets activated by TRAP or thrombin. Our present results indicate that GSE inhibits platelet signaling pathways trigged by both proteolytic (thrombin) and non-proteolytic agonist (TRAP). In the comparative studies, GSE was found to be more effective antiplatelet factor, than the solution of pure resveratrol. Thus, the polyphenol-rich extract from grape seeds can be useful as the protecting factor against cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are a primary cause of deaths worldwide. Thrombotic diseases, specifically stroke and coronary heart diseases, account for around 85% of CVDs-induced deaths. Platelets (small circulating blood cells) are responsible for the prevention of excessive bleeding upon vascular injury, through blood clotting (haemostasis). However, unnecessary activation of platelets under pathological conditions, such as upon the rupture of atherosclerotic plaques, results in thrombus formation (thrombosis), which can cause life threatening conditions such as stroke or heart attack. Therefore, antiplatelet medications are usually prescribed for people who are at a high risk of thrombotic diseases. The currently used antiplatelet drugs are associated with major side effects such as excessive bleeding, and some patients are resistant to these drugs. Therefore, numerous studies have been conducted to develop new antiplatelet agents and notably, to establish the relationship between edible plants, specifically fruits, vegetables and spices, and cardiovascular health. Indeed, healthy and balanced diets have proven to be effective for the prevention of CVDs in diverse settings. A high intake of fruits and vegetables in regular diet is associated with lower risks for stroke and coronary heart diseases because of their plethora of phytochemical constituents. In this review, we discuss the impacts of commonly used selected edible plants (specifically vegetables, fruits and spices) and/or their isolated compounds on the modulation of platelet function, haemostasis and thrombosis. [ABSTRACT FROM AUTHOR]

The recommended pharmacological therapy for patients with coronary artery disease (CAD) treated by coronary artery bypass grafting (CABG) is acetylsalicylic acid (ASA). To improve the antiplatelet effect, supplementation with flavonoids is also recommended. The aim of this study was to estimate anti-aggregation properties of diosmin, in combination with ASA, pre- and postoperatively and assess the relationship of this therapy with inflammatory processes in CAD patients undergoing CABG. The study patients (n = 26) took diosmin (1000 mg/day); the control patients (n = 27) took a placebo. The therapeutic period for taking diosmin was from at least 30 days before to 30 days after CABG. All patients also took 75 mg/day ASA. Platelet aggregation and IL-6, CRP, and fibrinogen concentrations were determined before and 30 days after surgery. Results showed that diosmin did not enhance the anti-aggregation effect of ASA at any assessment time. However, there was a stronger anti-aggregation effect 30 days after surgery that was diosmin independent and was associated with acute-phase markers in the postoperative period. Increased levels of inflammatory markers in the late phase of the postoperative period may provide an unfavorable prognostic factor in long-term follow-up, which should prompt the use of stronger antiplatelet therapy in patients after CABG. [ABSTRACT FROM AUTHOR]

The present study proposes to legitimize in sepsis a characteristic found in platelets that suffer storage lesions in blood banks, which is the increased expression of miRNA miR-320a in relation to miR-127. Under physiologically normal conditions, an inverse relationship is observed. The aim of this study was to verify whether the analysis of miR-320a and miR-127 expression in platelets could detect a decrease in their viability and function due to the presence of pathogens in the blood of patients hospitalized in the Intensive Care Unit. We also investigated the expression of membrane antigens sensitive to platelet activation. Of the 200 patients analyzed, only those who developed sepsis (140) were found to have a higher relative quantity of miR-320a than that of miR-127. This characteristic and the increased expression of membrane antigens P2Y12, CD62P, CD41, and CD61 showed a significant association (p < 0.01) with all types of sepsis evaluated in this study. Additionally, 40% of patients hospitalized for sepsis had negative results for the first cultures. We conclude that analysis of miR-127 and miR-320a expression combined with membrane antigens evaluation, in association with the available clinical and diagnostic parameters, are important tools to detect the onset of sepsis. [ABSTRACT FROM AUTHOR]

Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4+ T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A2 were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS. [ABSTRACT FROM AUTHOR]

Platelets are small anucleate blood cells that play vital roles in haemostasis and thrombosis, besides other physiological and pathophysiological processes. These roles are tightly regulated by a complex network of signalling pathways. Mass spectrometry-based proteomic techniques are contributing not only to the identification and quantification of new platelet proteins, but also reveal post-translational modifications of these molecules, such as acetylation, glycosylation and phosphorylation. Moreover, target proteomic analysis of platelets can provide molecular biomarkers for genetic aberrations with established or non-established links to platelet dysfunctions. In this report, we review 67 reports regarding platelet proteomic analysis and signalling on a molecular base. Collectively, these provide detailed insight into the: (i) technical developments and limitations of the assessment of platelet (sub)proteomes; (ii) molecular protein changes upon ageing of platelets; (iii) complexity of platelet signalling pathways and functions in response to collagen, rhodocytin, thrombin, thromboxane A2 and ADP; (iv) proteomic effects of endothelial-derived mediators such as prostacyclin and the anti-platelet drug aspirin; and (v) molecular protein changes in platelets from patients with congenital disorders or cardiovascular disease. However, sample sizes are still low and the roles of differentially expressed proteins are often unknown. Based on the practical and technical possibilities and limitations, we provide a perspective for further improvements of the platelet proteomic field. [ABSTRACT FROM AUTHOR]

Platelets are hematopoietic cells whose main function has for a long time been considered to be the maintenance of vascular integrity. They have an essential role in the hemostatic response, but they also have functional capabilities that go far beyond it. This review will provide an overview of platelet functions. Indeed, stress signals may induce platelet apoptosis through proapoptotis or hemostasis receptors, necrosis, and even autophagy. Platelets also interact with immune cells and modulate immune responses in terms of activation, maturation, recruitment and cytokine secretion. This review will also show that platelets, thanks to their wide range of innate immune receptors, and in particular toll-like receptors, and can be considered sentinels actively participating in the immuno-surveillance of the body. We will discuss the diversity of platelet responses following the engagement of these receptors as well as the signaling pathways involved. Finally, we will show that while platelets contribute significantly, via their TLRs, to immune response and inflammation, these receptors also participate in the pathophysiological processes associated with various pathogens and diseases, including cancer and atherosclerosis. [ABSTRACT FROM AUTHOR]

Epidemiological studies confirm a high risk of ischemic events in secondary-progressive multiple sclerosis (SP MS) patients, directly associated with an increased level of pro-thrombotic activity of platelets. Our work aimed to verify potential molecular abnormalities of the platelet P2Y12 receptor expression and functionality as a cause of an increased risk of thromboembolism observed in the course of MS. We have demonstrated an enhanced platelet reactivity in response to adenosine diphosphate (ADP) in SP MS relative to controls. We have also shown an increased mRNA expression for the P2RY12 gene in both platelets and megakaryocytes, as well as enhanced density of these receptors on the platelet surface. We postulate that one of the reasons for the elevated risk of ischemic events observed in MS may be a genetically or phenotypically reinforced expression of the platelet P2Y12 receptor. In order to analyze the effect of the PAR1 (protease activated receptor type 1) signaling pathway on the expression level of P2Y12, we also analyzed the correlation parameters between P2Y12 expression and the markers of platelet activation in MS induced by selective PAR1 agonist (thrombin receptor activating peptide-6, TRAP-6). Identifying the molecular base responsible for the enlarged pro-thrombotic activity of platelets in SP MS could contribute to the implementation of prevention and targeted treatment, reducing the development of cardiovascular disorders in the course of the disease. [ABSTRACT FROM AUTHOR]

The Pulmonaria species (lungwort) are edible plants and traditional remedies for different disorders of the respiratory system. Our work covers a comparative study on biological actions in human blood plasma and cyclooxygenase-2 (COX-2) -inhibitory properties of plant extracts (i.e., phenolic-rich fractions) originated from aerial parts of P. obscura Dumort. and P. officinalis L. Phytochemical profiling demonstrated the abundance of phenolic acids and their derivatives (over 80% of the isolated fractions). Danshensu conjugates with caffeic acid, i.e., rosmarinic, lithospermic, salvianolic, monardic, shimobashiric and yunnaneic acids were identified as predominant components. The examined extracts (1–100 µg/mL) partly prevented harmful effects of the peroxynitrite-induced oxidative stress in blood plasma (decreased oxidative damage to blood plasma components and improved its non-enzymatic antioxidant capacity). The cellular safety of the extracts was confirmed in experimental models of blood platelets and peripheral blood mononuclear cells. COX-2 inhibitor screening evidently suggested a stronger activity of P. officinalis (IC50 of 13.28 and 7.24 µg/mL, in reaction with synthetic chromogen and physiological substrate (arachidonic acid), respectively). In silico studies on interactions of main components of the Pulmonaria extracts with the COX-2 demonstrated the abilities of ten compounds to bind with the enzyme, including rosmarinic acid, menisdaurin, globoidnan A and salvianolic acid H. [ABSTRACT FROM AUTHOR]

Platelets are small pieces of cytoplasm that have become detached from the cytoplasm of mature megakaryocytes (MKs) in the bone marrow. Platelets modulate vascular system integrity and serve important role, particularly in hemostasis. With the rapid development of clinical medicine, the demand for platelet transfusion as a life-saving intervention increases continuously. Stem cell technology appears to be highly promising for transfusion medicine, and the generation of platelets from stem cells would be of great value in the clinical setting. Furthermore, several studies have been undertaken to investigate the potential of producing platelets from stem cells. Initial success has been achieved in terms of the yields and function of platelets generated from stem cells. However, the requirements of clinical practice remain unmet. The aim of the present review was to focus on several sources of stem cells and factors that induce MK differentiation. Updated information on current research into the genetic regulation of megakaryocytopoiesis and platelet generation was summarized. Additionally, advanced strategies of platelet generation were reviewed and the progress made in this field was discussed. [ABSTRACT FROM AUTHOR]

Epidemiological studies confirm the high risk of ischemic events in multiple sclerosis (MS) that are associated with increased pro-thrombotic activity of blood platelets. The most potent physiological platelet agonist is thrombin, which activates platelets via cleavage of specific protease-activated receptors (PARs). Our current study is aimed to determine the potential genetics and proteomic abnormalities of PAR1 in both platelets and megakaryocytes, which may have thromboembolic consequences in the course of MS. The obtained results were correlated with the expression level of platelet and megakaryocyte transcripts for APOA1 and A2M genes encoding atherosclerosis biomarkers: apolipoprotein A1 (ApoA1) and α-2-macroglobulin (α2M), respectively. Moreover, PAR1 functionality in MS platelets was assessed by flow cytometry, determining the level of platelet–platelet and platelet–leukocyte aggregates, platelet microparticles and surface expression of P-selectin. As a PAR1 agonist, the synthetic TRAP-6 peptide was used, which made it possible to achieve platelet activation in whole blood without triggering clotting. Comparative analyses showed an elevated level of platelet activation markers in the blood of MS patients compared to controls. The mRNA expression of gene coding α2M was upregulated, whilst ApoA1 was down-regulated, both in platelets and megakaryocytes from MS patients. Furthermore, we observed an increase in both mRNA expression and surface density of PAR1 in platelets and megakaryocytes in MS compared to controls. Both the level of platelet activation markers and PAR1 expression showed a high correlation with the expression of transcripts for APOA1 and A2M genes. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) and mitochondria play a pivotal role in regulating platelet functions. Platelet activation determines a drastic change in redox balance and in platelet metabolism. Indeed, several signaling pathways have been demonstrated to induce ROS production by NAPDH oxidase (NOX) and mitochondria, upon platelet activation. Platelet-derived ROS, in turn, boost further ROS production and consequent platelet activation, adhesion and recruitment in an auto-amplifying loop. This vicious circle results in a platelet procoagulant phenotype and apoptosis, both accounting for the high thrombotic risk in oxidative stress-related diseases. This review sought to elucidate molecular mechanisms underlying ROS production upon platelet activation and the effects of an altered redox balance on platelet function, focusing on the main advances that have been made in platelet redox biology. Furthermore, given the increasing interest in this field, we also describe the up-to-date methods for detecting platelets, ROS and the platelet bioenergetic profile, which have been proposed as potential disease biomarkers. [ABSTRACT FROM AUTHOR]

Besides their vital role in hemostasis and thrombosis, platelets are also recognized to be involved in cancer, where they play an unexpected central role: They actively influence cancer cell behavior, but, on the other hand, platelet physiology and phenotype are impacted by tumor cells. The existence of this platelet-cancer loop is supported by a large number of experimental and human studies reporting an association between alterations in platelet number and functions and cancer, often in a way dependent on patient, cancer type and treatment. Herein, we shall report on an update on platelet-cancer relationships, with a particular emphasis on how platelets might exert either a protective or a deleterious action in all steps of cancer progression. To this end, we will describe the impact of (i) platelet count, (ii) bioactive molecules secreted upon platelet activation, and (iii) microvesicle-derived miRNAs on cancer behavior. Potential explanations of conflicting results are also reported: Both intrinsic (heterogeneity in platelet-derived bioactive molecules with either inhibitory or stimulatory properties; features of cancer cell types, such as aggressiveness and/or tumour stage) and extrinsic (heterogeneous characteristics of cancer patients, study design and sample preparation) factors, together with other confounding elements, contribute to "the Janus face" of platelets in cancer. Given the difficulty to establish the univocal role of platelets in a tumor, a better understanding of their exact contribution is warranted, in order to identify an efficient therapeutic strategy for cancer management, as well as for better prevention, screening and risk assessment protocols. [ABSTRACT FROM AUTHOR]

Platelets and platelet microparticles (PMPs) play a key role in the pathophysiology of vascular disorders such as coronary artery disease and stroke. In atherosclerosis, for example, the disruption of the plaque exposes endogenous agonists such as collagen, which activates platelets. Platelet hyper-activation and the high levels of PMPs generated in such situations pose a thrombotic risk that can lead to strokes or myocardial infarctions. Interestingly, dietary polyphenols are gaining much attention due to their potential to mimic the antiplatelet activity of treatment drugs such as aspirin and clopidogrel that target the glycoprotein VI (GPVI)–collagen and cyclooxygenease-1 (COX-1)–thromboxane platelet activation pathways respectively. Platelet function tests such as aggregometry and flow cytometry used to monitor the efficacy of antiplatelet drugs can also be used to assess the antiplatelet potential of dietary polyphenols. Despite the low bioavailability of polyphenols, several in vitro and dietary intervention studies have reported antiplatelet effects of polyphenols. This review presents a summary of platelet function in terms of aggregation, secretion, activation marker expression, and PMP release. Furthermore, the review will critically evaluate studies demonstrating the impact of polyphenols on aggregation and PMP release. [ABSTRACT FROM AUTHOR]

The available data, including experimental studies, clearly indicate an excessive intravascular activation of circulating platelets in multiple sclerosis (MS) and their hyper-responsiveness to a variety of physiological activators. Platelet activation is manifested as an increased adhesion and aggregation and is accompanied by the formation of pro-thrombotic microparticles. Activated blood platelets also show an expression of specific membrane receptors, synthesis many of biomediators, and generation of reactive oxygen species. Epidemiological studies confirm the high risk of stroke or myocardial infarction in MS that are ischemic incidents, strictly associated with incorrect platelet functions and their over pro-thrombotic activity. Chronic inflammation and high activity of pro-oxidative processes in the course of MS are the main factors identified as the cause of excessive platelet activation. The primary biological function of platelets is to support vascular integrity, but the importance of platelets in inflammatory diseases is also well documented. The pro-thrombotic activity of platelets and their inflammatory properties play a part in the pathophysiology of MS. The analysis of platelet function capability in MS could provide useful information for studying the pathogenesis of this disease. Due to the complexity of pathological processes in MS, medication must be multifaceted and blood platelets can probably be identified as new targets for therapy in the future. [ABSTRACT FROM AUTHOR]

The population is now living longer during the period classified as "elderly" (60 years and older), exhibiting multimorbidity associated to the lengthening of the average life span. The dietary intake of phenolic compounds (PC) may affect the physiology, disease development and progression during the aging process, reducing risk factors of age related diseases. The aim of this review is to briefly describe some of the possible effects of a series of PC on the reduction of risk factors of the onset of cardiovascular diseases, considering their potential mechanisms of action. The main actions described for PC are associated with reduced platelet activity, anti-inflammatory effects, and the protection from oxidation to reduce LDL and the generation of advanced glycation end products. Preclinical and clinical evidence of the physiological effects of various PC is presented, as well as the health claims approved by regulatory agencies. [ABSTRACT FROM AUTHOR]