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Physiological Research Mar 2022Exposure to high altitudes and exercise alters body's physiology and may cause acute cardiovascular events. Platelet activation is one of the key players in these...
Exposure to high altitudes and exercise alters body's physiology and may cause acute cardiovascular events. Platelet activation is one of the key players in these events. Therefore, we investigated the effect of vigorous exercise at higher altitude (2650 m) on platelet aggregation and serum markers of platelet activation. 14 healthy subjects performed a step incremental ergometer test until exhaustion at the Environmental Research Station (UFS, 2650 m) at Zugspitze. Platelet aggregation and serum levels of endothelin-1, soluble p-selectin, platelet factor 4 and Chromogranin A were measured. Platelet activation was significantly enhanced after exercise at high altitude compared to measures immediately prior exercise. We detected significantly enhanced serum levels of endothelin-1 and soluble p-selectin whereas chromogranin A and platelet factor 4 remained unchanged. This effect might be due to increased endothelin-1 levels causing pulmonary vasoconstriction, rheological changes and direct platelet activation. This might be of clinical relevance, especially in patients with pre-existing diseases.
Topics: Altitude; Exercise; Humans; P-Selectin; Platelet Activation; Platelet Aggregation
PubMed: 35043652
DOI: 10.33549/physiolres.934768 -
Frontiers in Immunology 2022Platelets have essential functions as first responders in the immune response to pathogens. Activation and aggregation of platelets in bacterial infections can lead to...
INTRODUCTION
Platelets have essential functions as first responders in the immune response to pathogens. Activation and aggregation of platelets in bacterial infections can lead to life-threatening conditions such as arterial thromboembolism or sepsis-associated coagulopathy.
METHODS
In this study, we investigated the role of complement in (-induced platelet aggregation in human whole blood, using Multiplate aggregometry, flow cytometry, and confocal microscopy.
RESULTS AND DISCUSSION
We found that compstatin, which inhibits the cleavage of complement component C3 to its components C3a and C3b, reduced the -induced platelet aggregation by 42%-76% (p = 0.0417). This C3-dependent aggregation was not C3a-mediated as neither inhibition of C3a using a blocking antibody or a C3a receptor antagonist, nor the addition of purified C3a had any effects. In contrast, a C3b-blocking antibody significantly reduced the -induced platelet aggregation by 67% (p = 0.0133). We could not detect opsonized C3b on platelets, indicating that the effect of C3 was not dependent on C3b-fragment deposition on platelets. Indeed, inhibition of glycoprotein IIb/IIIa (GPIIb/IIIa) and complement receptor 1 (CR1) showed that these receptors were involved in platelet aggregation. Furthermore, aggregation was more pronounced in hirudin whole blood than in hirudin platelet-rich plasma, indicating that -induced platelet aggregation involved other blood cells. In conclusion, the -induced platelet aggregation in human whole blood is partly C3b-dependent, and GPIIb/IIIa and CR1 are also involved in this process.
Topics: Humans; Blood Platelets; Complement C3b; Escherichia coli; Hirudins; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; In Vitro Techniques
PubMed: 36591264
DOI: 10.3389/fimmu.2022.1020712 -
Scientific Reports Dec 2019NADPH oxidase (NOX) enzymes are involved in a various physiological and pathological processes such as platelet activation and inflammation. Interestingly, we found that...
NADPH oxidase (NOX) enzymes are involved in a various physiological and pathological processes such as platelet activation and inflammation. Interestingly, we found that the pan-NOX inhibitors VAS compounds (VAS2870 and its analog VAS3947) exerted a highly potent antiplatelet effect. Unlike VAS compounds, concurrent inhibition of NOX1, 2, and 4 by treatment with ML171, GSK2795039, and GKT136901/GKT137831 did not affect thrombin and U46619-induced platelet aggregation. These findings suggest that VAS compounds may inhibit platelet aggregation via a NOX-independent manner. Thus, we aimed to investigate the detailed antiplatelet mechanisms of VAS compounds. The data revealed that VAS compounds blocked various agonist-induced platelet aggregation, possibly via blocking PKC downstream signaling, including IKKβ and p38 MAPK, eventually reducing platelet granule release, calcium mobilization, and GPIIbIIIa activation. In addition, VAS compounds inhibited mouse platelet aggregation-induced by collagen and thrombin. The in vivo study also showed that VAS compounds delayed thrombus formation without affecting normal hemostasis. This study is the first to demonstrate that, in addition to inhibiting NOX activity, VAS compounds reduced platelet activation and thrombus formation through a NOX-independent pathway downstream of PKC. These findings also indicate that VAS compounds may be safe and potentially therapeutic agents for treating patients with cardiovascular diseases.
Topics: Animals; Benzoxazoles; Humans; Male; Mice; NADPH Oxidases; Platelet Aggregation; Protein Kinase C; Pyrimidines; Signal Transduction; Thrombosis; Triazoles
PubMed: 31827142
DOI: 10.1038/s41598-019-55189-5 -
Journal of Thrombosis and Haemostasis :... Nov 2020Amyloid peptides Aβ40 and Aβ42, whose deposition in brain correlates with Alzheimer disease, are also present in platelets and have prothrombotic activities.
BACKGROUND
Amyloid peptides Aβ40 and Aβ42, whose deposition in brain correlates with Alzheimer disease, are also present in platelets and have prothrombotic activities.
OBJECTIVE
In this study, we analyze the ability of Aβ peptides to form fibrils and to induce platelet activation and aggregation.
METHODS
Aβ40, Aβ42, and their scrambled peptides were diluted in phosphate buffered saline and fibrillogenesis was investigated by ThioflavinT and Congo Red. Aggregation, protein phosphorylation, and reactive oxygen species (ROS) production were analyzed.
RESULTS
Aβ40 and Aβ42, but not scrambled peptides, were able to form fibrils when diluted in phosphate buffered saline. Fibrillogenesis of Aβ42 was very rapid, whereas fibril formation by Aβ40 was completed only after 48 hours of incubation. Fibrillar Aβ40 and Aβ42 promoted dose-dependent aggregation of washed platelets in the presence of extracellular CaCl . Cleavage of GPIbα by mocarhagin or blockade of the ITAM-containing FcγRIIA prevented platelet aggregation induced by fibrillary Aβ40 and Aβ42. Fibrillar Aβ peptides stimulated the phosphorylation of FcγRIIA, resulting in the downstream stimulation of PLC, protein kinase C, and phosphoinositide 3-kinases, whose activity was necessary for full aggregation of platelets. Fibrillar Aβ peptides also induced ROS generation, and NOX inhibitors, as well as ROS scavengers, prevented platelet aggregation. However, Aβ peptide-induced ROS production did not require binding to GPIbα or activation of FcγRIIA, but was initiated by CD36, which provided an important contribution to full platelet aggregation.
CONCLUSION
These results suggest that fibrillar amyloid Aβ40 and Aβ42 induce platelet aggregation through the recruitment of GPIb-IX-V and CD36, which requires the convergence of ITAM- and ROS-dependent pathways.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Humans; Peptide Fragments; Platelet Aggregation; Reactive Oxygen Species
PubMed: 32790050
DOI: 10.1111/jth.15055 -
Nanotoxicology May 2015Nanoparticles (NPs) may come into contact with circulating blood elements including platelets following inhalation and translocation from the airways to the bloodstream...
Nanoparticles (NPs) may come into contact with circulating blood elements including platelets following inhalation and translocation from the airways to the bloodstream or during proposed medical applications. Studies with model polystyrene latex nanoparticles (PLNPs) have shown that NPs are able to induce platelet aggregation in vitro suggesting a poorly defined potential mechanism of increased cardiovascular risk upon NP exposure. We aimed to provide insight into the mechanisms by which NPs may increase cardiovascular risk by determining the impact of a range of concentrations of PLNPs on platelet activation in vitro and in vivo and identifying the signaling events driving NP-induced aggregation. Model PLNPs of varying nano-size (50 and 100 nm) and surface chemistry [unmodified (uPLNP), amine-modified (aPLNP) and carboxyl-modified (cPLNP)] were therefore examined using in vitro platelet aggregometry and an established mouse model of platelet thromboembolism. Most PLNPs tested induced GPIIb/IIIa-mediated platelet aggregation with potencies that varied with both surface chemistry and nano-size. Aggregation was associated with signaling events, such as granule secretion and release of secondary agonists, indicative of conventional agonist-mediated aggregation. Platelet aggregation was associated with the physical interaction of PLNPs with the platelet membrane or internalization. 50 nm aPLNPs acted through a distinct mechanism involving the physical bridging of adjacent non-activated platelets leading to enhanced agonist-induced aggregation in vitro and in vivo. Our study suggests that should they translocate the pulmonary epithelium, or be introduced into the blood, NPs may increase the risk of platelet-driven events by inducing or enhancing platelet aggregation via mechanisms that are determined by their distinct combination of nano-size and surface chemistry.
Topics: Animals; In Vitro Techniques; Mice; Nanoparticles; Platelet Aggregation; Polystyrenes
PubMed: 25030098
DOI: 10.3109/17435390.2014.933902 -
Scientific Reports Oct 2022The physiological effect of Lp(a) on platelet activity is unclear. Previous studies explored the relationship between Lp(a) and platelet aggregation in patients taking...
The physiological effect of Lp(a) on platelet activity is unclear. Previous studies explored the relationship between Lp(a) and platelet aggregation in patients taking statins and antiplatelet agents, but few was conducted in individuals without the bias of those drugs that either influence Lp(a) or platelet activity. The aim of this study was to assess the relationship between Lp(a) levels and platelet aggregation in subjects not taking statins or antiplatelet drugs. A hospital-based cross-sectional study was conducted to investigate the independent contribution of Lp(a) to platelet activity by controlling the effects of potential confounding factors including lipoprotein-associated phospholipase A2 [Lp-PLA2]. Blood samples were collected from 92 subjects without statins or antiplatelet agents from the Second Xiangya Hospital. The univariate correlation analysis showed a significant correlation between AA-induced average aggregation rate [AAR] and ApoB (r = 0.324, P = 0.002), ApoA1 (r = 0.252, P = 0.015), Lp(a) (r = 0.370, P < 0.001), Lp-PLA2 (r = 0.233, P = 0.025) and platelet counts [PLT] (r = 0.389, P < 0.001). Multivariate regression analysis suggested that Lp(a) contributed independently to AA-induced average aggregation rate (β = 0.023, P = 0.027) after controlling for the effects of ApoB, Lp-PLA2 and platelet counts. Lp(a) is positively associated with platelet aggregation independent of Lp-PLA2, which may partly account for the atherothrombotic effect of Lp(a).
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Biomarkers; Cross-Sectional Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Platelet Aggregation; Platelet Aggregation Inhibitors; Risk Factors
PubMed: 36198899
DOI: 10.1038/s41598-022-21121-7 -
Clinical and Applied... 2020Edoxaban, a direct factor Xa inhibitor (FXa), is the fourth direct oral anticoagulant (DOAC) approved for clinical use. As the main adverse event is bleeding, it is...
Edoxaban, a direct factor Xa inhibitor (FXa), is the fourth direct oral anticoagulant (DOAC) approved for clinical use. As the main adverse event is bleeding, it is relevant whether edoxaban has additional effects on platelet function. We aimed to assess in vitro aggregation in patients with atrial fibrillation (AF) receiving edoxaban. We evaluated 20 AF patients treated with edoxaban. We assessed light transmittance platelet aggregation (LTA) with 100 nmol/L γ-thrombin. The LTA was performed at 2 time-points. The thrombin-induced platelet aggregation was significantly lower 2 hours after edoxaban was taken compared to baseline measurement (27.25% ± 30.8% vs. 60.35% ± 33.3%). In addition, we also performed 16 subanalyses in order to identify the differences in the outcome of different comorbidities, age, dosage, liver and kidney function tests, and concomitant treatment. Results of the subgroup analyses were consistent with the findings of the main analysis; there was no apparent heterogeneity across the prespecified subgroups. The thrombin-induced platelet aggregation is reduced in non-valvular AF patients receiving edoxaban.
Topics: Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Platelet Aggregation; Pyridines; Thiazoles
PubMed: 33054412
DOI: 10.1177/1076029620948585 -
British Journal of Pharmacology Apr 2021The pathophysiology of coronary artery spasm (CAS), with its associated ischaemic crises, is currently poorly understood and treatment is frequently ineffective. In view...
BACKGROUND AND PURPOSE
The pathophysiology of coronary artery spasm (CAS), with its associated ischaemic crises, is currently poorly understood and treatment is frequently ineffective. In view of increasing evidence that platelet-based defects may occur in CAS patients, we investigated platelet reactivity in CAS patients and whether symptomatic crises reflect activation of platelet-endothelial interactions.
EXPERIMENTAL APPROACH
CAS patients were evaluated during acute and/or chronic symptomatic phases and compared with healthy control subjects. Inhibition of ADP-induced platelet aggregation by the NO donor sodium nitroprusside (SNP) and plasma concentrations of syndecan 1 (glycocalyx shedding marker), tryptase (mast cell activation marker) and platelet microparticles were measured.
KEY RESULTS
Inhibition of platelet aggregation by SNP was diminished in chronic CAS, with further (non-significant) deterioration during symptomatic crises, whereas plasma concentrations of syndecan 1, tryptase and platelet microparticles increased. Treatment of patients with high-dose N-acetylcysteine (NAC) plus glyceryl trinitrate rapidly increased platelet responsiveness to SNP and decreased plasma syndecan 1 concentrations. The effect of NAC on platelet responsiveness to SNP was confirmed in vitro and mimicked by the H S donor NaHS. Conversely, inhibition of enzymatic production of H S attenuated NAC effect.
CONCLUSION AND IMPLICATIONS
CAS is associated with substantial impairment of platelet NO signalling. During acute symptomatic exacerbations, platelet resistance to NO is aggravated, together with mast cell activation and damage to both vasculature and platelets. NAC, via release of H S, reverses platelet resistance to NO and terminates glycocalyx shedding during symptomatic crises: This suggests that H S donors may correct the pathophysiological anomalies underlying CAS.
Topics: Blood Platelets; Coronary Vessels; Humans; Hydrogen Sulfide; Platelet Aggregation; Platelet Aggregation Inhibitors; Spasm
PubMed: 33486763
DOI: 10.1111/bph.15388 -
Journal of Thrombosis and Haemostasis :... Nov 2020Metastatic prostate cancer progresses from a hormone sensitive androgen receptor expressing phenotype to a hormone insensitive androgen receptor-independent subtype with...
BACKGROUND
Metastatic prostate cancer progresses from a hormone sensitive androgen receptor expressing phenotype to a hormone insensitive androgen receptor-independent subtype with low overall survival. Human platelets contribute to metastasis via tumor cell-induced platelet aggregation, which in part enhances cancer cell invasion. Given the more aggressive nature of hormone insensitive prostate cancer, we hypothesized that androgen receptor-negative prostate cancer cells exhibit higher platelet aggregation potency and invasive response compared to cells with androgen receptor.
OBJECTIVE
To characterize the role of androgen receptors in prostate cancer-induced platelet aggregation and platelet-induced invasion.
METHODS
Tumor cell-induced platelet aggregation experiments were performed with platelets from healthy human donors and benign prostate (RWPE-1) and prostate cancer cell lines positive (LNCaP) and negative for androgen receptor (DU145 and PC3). Immunoblot measured prostate cancer prothrombin. Modified Boyden chamber invasion assays and zymography were performed to assess the effects of platelets on prostate cancer cell invasion and matrix metalloproteinase (MMP) expression, respectively.
RESULTS
Androgen receptor-positive prostate cancer cell lines failed to induce platelet aggregation. However, androgen receptor-inhibited and -negative cell lines all induced platelet aggregation, which was abolished by dabigatran. Androgen receptor-inhibited and -negative cell lines demonstrated greater expression of prothrombin than androgen receptor-positive cells. Platelets enhanced invasion and MMP-2 and -9 expression by androgen receptor-inhibited and negative prostate cancer cells, but not that of the androgen receptor-positive cells.
CONCLUSIONS
Androgen receptor loss within prostate cancer results in increased thrombogenicity due to upregulation of prothrombin expression. Reciprocally, platelets enhance invasion of androgen receptor-negative prostate cancer cells via increased MMP expression.
Topics: Blood Platelets; Cell Line, Tumor; Cell Proliferation; Humans; Male; Platelet Aggregation; Prostatic Neoplasms; Receptors, Androgen
PubMed: 32692888
DOI: 10.1111/jth.15020 -
European Review For Medical and... May 2018Several adipokines secreted by adipose tissue have an anti-thrombotic and anti-atherosclerotic function. Recently identified adipokine progranulin was found to play a...
OBJECTIVE
Several adipokines secreted by adipose tissue have an anti-thrombotic and anti-atherosclerotic function. Recently identified adipokine progranulin was found to play a protective role in atherosclerosis. Bearing in mind the central role of platelets in inflammation and atherosclerosis, we aimed, in this study, to examine the effect of progranulin on platelet function and coagulation profile in rats.
MATERIALS AND METHODS
Healthy male albino Wistar rats weighing (250-300 g) were divided into 4 groups. Three groups were given increasing doses of progranulin (0.001 µg, 0.01 µg, and 0.1 µg) intraperitoneally, while the control group received phosphate-buffered saline (PBS). Bleeding time, prothrombin time, activated partial thromboplastin time and platelet aggregation responses to adenosine diphosphate and arachidonic acid were assessed.
RESULTS
Administration of progranulin resulted in a significant inhibition of platelet aggregation in response to both adenosine diphosphate, and arachidonic acid. Bleeding time, prothrombin time and activated partial thromboplastin time were significantly prolonged in all groups that received progranulin, in particular, the 0.1 µg dose, in comparison to the control group.
CONCLUSIONS
This preliminary data is first suggesting that the antiplatelet and anticoagulant action of progranulin could have a physiological protective function against thrombotic disorders associated with obesity and atherosclerosis. However, these results merit further exploration.
Topics: Adenosine Diphosphate; Animals; Arachidonic Acid; Bleeding Time; Hemostasis; Humans; Male; Partial Thromboplastin Time; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Progranulins; Prothrombin Time; Rats
PubMed: 29863272
DOI: 10.26355/eurrev_201805_15087