scholarly journals Shear-mediated platelet activation in patients implanted with continuous flow LVADs: A preliminary study utilizing the platelet activity state (PAS) assay

2015 ◽  
Author(s):  
Lorenzo Valerio ◽  
Filippo Consolo ◽  
Danny Bluestein ◽  
Phat Tran ◽  
Marvin Slepian ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Continuous Flow ◽  
Platelet Activity ◽  
Preliminary Study ◽  
Activity State

Platelet Activation and Free Emboli Formation in Flow Past Mechanical Heart Valves

2002 ◽  
Author(s):  
Danny Bluestein ◽  
Wei Yin ◽  
Jolyon Jesty ◽  
Adam E. Saltman ◽  
Irvin B. Krukenkamp ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Heart Valves ◽  
Left Ventricular ◽  
Mechanical Heart Valves ◽  
Shear Stresses ◽  
Platelet Activity ◽  
Flow Past ◽  
Activity State ◽  
Valve Implantation

Numerical studies, in vitro, and in vivo measurements were conducted, aimed at quantifying free emboli formation and procoagulant properties of platelets induced by flow past mechanical heart valves (MHV). Pulsatile turbulent flow simulation was conducted past a St. Jude medical MHV in the aortic position, to study the effects of valve implantation technique on the thromboembolic potential of the valve. A misaligned valve with subannualarly sutured pledgets produced accelerating jet flow through the valve orifices and a wider wake of shed vortices. Shear stress histories of platelets along turbulent trajectories exposed the platelets to elevated shear stresses around the leaflets, leading them to entrapment within the shed vortices. In vitro platelet studies were conducted past the MHV mounted in a recirculation flow loop and in a model of left ventricular assist device (LVAD), using an innovative platelet activity state (PAS) assay. The platelet activation significantly increased as a function of the recirculation time past the valve, and as compared to controls. Transcranial Doppler (TCD) measurements were conducted in the carotid artery of sheep with implanted MHV, showing marked increase in the number of HITS (High Intensity Transient Signals) signifying the passage of free emboli generated by the valve. The HITS were analyzed to distinguish between gaseous and thrombi emboli. Finally, platelet activity state measurements were conducted with sheep platelets, showing marked increase of platelet activation after valve implantation.

scholarly journals On the Use of the Platelet Activity State Assay for the In Vitro Quantification of Platelet Activation in Blood Recirculating Devices for Extracorporeal Circulation

2016 ◽  
Vol 40 (10) ◽  
pp. 971-980 ◽  
Author(s):  
Filippo Consolo ◽  
Lorenzo Valerio ◽  
Stefano Brizzola ◽  
Paolo Rota ◽  
Giulia Marazzato ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Extracorporeal Circulation ◽  
Platelet Activity ◽  
Activity State

569 Preliminary Study: Increased Levels of cGMP in Recipients of Continuous Flow LVADs, Implications for Gastrointestinal Bleeding

2012 ◽  
Vol 31 (4) ◽  
pp. S197
Author(s):  
L. Grosman-Rimon ◽  
D.Z.I. Cherney ◽  
S. Pollock Bar-Ziv ◽  
M.A. McDonald ◽  
L. Tumiati ◽  
...  
Keyword(s):  
Gastrointestinal Bleeding ◽  
Continuous Flow ◽  
Preliminary Study

Abstract 5451: Deficiency of Glutathione Peroxidase-3 Promotes Platelet Activation in vivo

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Richard C Jin ◽  
Christopher E Mahoney ◽  
Laura Coleman ◽  
Filomena G Ottaviano ◽  
Yingyi Zhang ◽  
...  
Keyword(s):  
Glutathione Peroxidase ◽  
Platelet Activation ◽  
Oxidant Stress ◽  
Antioxidant Properties ◽  
Soluble Guanylyl Cyclase ◽  
Pulmonary Vasculature ◽  
Wild Type ◽  
Platelet Activity ◽  
Induce Platelet Aggregation

Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing protein with antioxidant properties. GPx-3 plays an important role in plasma against oxidant stress by scavenging reactive oxygen species. A deficiency of this enzyme has been associated with platelet dependent thrombosis. We recently developed an animal model to assess platelet function in GPx-3 deficient mice. We hypothesized that GPx-3 deficiency induces platelet activation in vivo . GPx-3 (−/−) mice showed an attenuated bleeding time compared with wild-type mice (94.5 ± 28.8 s versus 153.4 ± 32.3, P<0.05). We also noted an increase in the plasma levels of soluble P-selectin, a marker of platelet activation and prothrombotic activity, in GPx-3 (−/−) mice compared with wild-type mice (137.8 ± 12.3 ng/ml plasma versus 101.5 ± 8.8, P<0.05). Cyclic GMP, a key intracellular second messenger molecule and marker for activation of soluble guanylyl cyclase by nitric oxide, was decreased in the plasma of GPx-3 (−/−) mice compared with wild-type mice (5.38 ± 1.75 pmol/ml plasma versus 23.67 ± 3.59, P<0.001), consistent with less bioactive NO in GPx-3 (−/−) mice. ADP was infused into the right ventricle of mice to induce platelet aggregation in the pulmonary vasculature; this assay resulted in higher pulmonary artery pressure in GPx-3 (−/−) compared with wild-type mice suggesting a more robust platelet activation response in the GPx-3 (−/−) mice. To confirm this interpretation, histological sections from the pulmonary vasculature of GPx-3 (−/−) compared with wild-type mice showed increased thrombi per 7.5 mm 2 section normalized to wild-type mice based on staining intensity for P-selectin (1.7 ± 0.4 versus 1.0 ± 0.1, P<0.001), as well as a higher percentage of occluded vessels (0.82 ± 0.16 % versus 0.54 ± 0.21, P<0.05). These findings demonstrate that GPx-3 deficiency causes platelet activation resulting in a prothrombotic state. These data illustrate the importance of this plasma antioxidant enzyme in regulating platelet activity and platelet-dependent thrombosis.

scholarly journals Short fungal fractions of β-1,3 glucans affect platelet activation

2016 ◽  
Vol 311 (3) ◽  
pp. H725-H734 ◽  
Author(s):  
Hélène Vancraeyneste ◽  
Rogatien Charlet ◽  
Yann Guerardel ◽  
Laura Choteau ◽  
Anne Bauters ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Atp Release ◽  
Human Platelets ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Platelet Activity ◽  
Concentration Dependent Manner ◽  
Wide Range ◽  
Invasive Infections ◽  
Life Threatening

Platelets are capable of binding, aggregating, and internalizing microorganisms, which enhances the elimination of pathogens from the blood. The yeast Candida albicans is a pathobiont causing life-threatening invasive infections. Its cell wall contains β-1,3 glucans that are known to trigger a wide range of host cell activities and to circulate during infection. We studied the effect of β-1,3 glucan fractions (BGFs) consisting of diglucosides (Glc2), tetraglucosides (Glc4), and pentaglucosides (Glc5) on human platelets, their mechanisms of action, and their possible impact on host defenses. The effect of BGFs on the coagulation process was determined by measuring thrombin generation. Platelets pretreated with BGFs were analyzed in terms of activation, receptor expression, aggregation, and adhesion to neutrophils and to C. albicans. The results show that BGFs affected the endogenous thrombin potential in a concentration-dependent manner. For platelet activation, BGFs at a low concentration (2 μmol/l) reduced ATP release and prevented the phosphorylation of protein kinase C. BGFs diminished the expression of P-selectin and the activation of αIIbβ3. BGFs decreased platelet aggregation and the interaction between thrombin-stimulated platelets and neutrophils, fibrinogen, and C. albicans. GLc5 decreased ATP release and TGF-β1 production in response to TLR4 upregulation in thrombin-stimulated platelets, but TLR4 blockage abolished the effect of BGFs on platelets. This study provides evidence that fungal pentaglucosides modulate platelet activity mediated via TLR4 stimulation and reduce platelet-neutrophil interaction.

Abstract 492: Arachidonic Acid Induces Activation of Platelet PF4 and Par-1 mRNA, Which Is Attenuated by Aspirin

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Liang Hu ◽  
Michael A Nardi ◽  
Michael Merolla ◽  
Yajaira Suarez ◽  
Jeffrey Berger
Keyword(s):  
Arachidonic Acid ◽  
Platelet Activation ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Thiazole Orange ◽  
Platelet Activity ◽  
Protein Levels ◽  
Reticulated Platelets ◽  
Mrna And Protein Expression ◽  
Dose Dependent

Arachidonic acid (AA) is converted to thromboxane A2 via the cyclooxygenase pathway; however its exact mechanism of platelet activation is uncertain. Inhibition of this pathway via aspirin highlights the importance of this pathway in decreasing thrombotic events. In the present study, we investigate the effect of AA on platelet activity indicators (leukocyte- and monocyte-platelet aggregation [LPA, MPA] and reticulated platelets [RP]), as well as the expression (mRNA and protein) of platelet markers PF4 and Par-1, previously well established platelet transcripts with quantitative determinations. To this end, whole blood was incubated with AA (150mM) for 30 min at room temperature in the absence or presence of aspirin (1mM) prior to addition of antibodies for platelet activity indicators, and isolating platelets for mRNA and protein expression. LPA and MPA were significantly increased after AA stimulation in a dose dependent manner, and were inhibited by aspirin treatment. AA significantly increased PF4 and Par-1 protein level as determined by flow cytometry and western blot assays. Pretreatment with aspirin also attenuated this increase in protein levels. Surprisingly, AA stimulation significantly increased thiazole orange staining (a measure of nucleic acids), another marker of increased platelet activity. Importantly, these results suggest that AA-mediated platelet activation produced an overall increase in platelet total RNA content. To confirm these findings, we analyzed the mRNA expression of PF4 and Par-1 by quantitative real time PCR from platelets treated with AA. Interestingly, AA significantly up-regulated the platelet mRNA transcripts of PF4 and Par-1 by 40% to 60%, and pretreatment with aspirin completely attenuated this effect supporting the specificity of the AA effect on platelet RNA. Altogether, these data suggest that platelet mRNA is affected by AA stimulation, which is attenuated by pretreatment with aspirin. However, the mechanisms responsible for the increased mRNA levels and expression of PF4 and Par-1 (processing of pre-RNA to mRNA) require further investigation. Importantly, our findings provide novel insight regarding platelet activation and a better understanding of mediators in the processes of thrombosis and hemostasis.

scholarly journals Black Sorghum Phenolic Extract Modulates Platelet Activation and Platelet Microparticle Release

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1760 ◽  
Author(s):  
Borkwei Ed Nignpense ◽  
Kenneth A Chinkwo ◽  
Christopher L Blanchard ◽  
Abishek B Santhakumar
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Conformational Changes ◽  
Thrombus Formation ◽  
Antiplatelet Agents ◽  
Limited Information ◽  
Platelet Activity ◽  
Dietary Polyphenols ◽  
High Antioxidant Activity ◽  
Phenolic Extract

Platelet hyper-activation and platelet microparticles (PMPs) play a key role in the pathogenesis of cardiovascular diseases. Dietary polyphenols are believed to mimic antiplatelet agents by blunting platelet activation receptors via its antioxidant phenomenon. However, there is limited information on the anti-platelet activity of grain-derived polyphenols. The aim of the study is to evaluate the effects of sorghum extract (Shawaya short black 1 variety), an extract previously characterised for its high antioxidant activity and reduction of oxidative stress-related endothelial dysfunction, on platelet aggregation, platelet activation and PMP release. Whole blood samples collected from 18 healthy volunteers were treated with varying non-cytotoxic concentrations of polyphenol-rich black sorghum extract (BSE). Platelet aggregation study utilised 5 µg/mL collagen to target the GPVI pathway of thrombus formation whereas adenine phosphate (ADP) was used to stimulate the P2Y1/P2Y12 pathway of platelet activation assessed by flow cytometry. Procaspase-activating compound 1 (PAC-1) and P-selectin/CD62P were used to evaluate platelet activation- related conformational changes and degranulation respectively. PMPs were isolated from unstimulated platelets and quantified by size distribution and binding to CD42b. BSE treatment significantly reduced both collagen-induced platelet aggregation and circulatory PMP release at 40 µg/mL (p < 0.001) when compared to control. However, there was no significant impact of BSE on ADP-induced activation-dependent conformational change and degranulation of platelets. Results of this study suggest that phenolic rich BSE may confer cardio-protection by modulating specific signalling pathways involved in platelet activation and PMP release.

scholarly journals Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets

Circulation ◽  
2020 ◽  
Vol 142 (1) ◽  
pp. 49-64 ◽  
Author(s):  
Yanyan Xu ◽  
Haojie Jiang ◽  
Li Li ◽  
Fengwu Chen ◽  
Yunxia Liu ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Platelet Activation ◽  
Protein Phosphatase ◽  
Arterial Thrombosis ◽  
Chinese Hamster Ovary Cells ◽  
Platelet Activity ◽  
Integrin Αiibβ3 ◽  
Thrombosis Risk ◽  
Mass Spectrometry Identification ◽  
Branched Chain

Background: Branched-chain amino acids (BCAAs), essential nutrients including leucine, isoleucine, and valine, serve as a resource for energy production and the regulator of important nutrient and metabolic signals. Recent studies have suggested that dysfunction of BCAA catabolism is associated with the risk of cardiovascular disease. Platelets play an important role in cardiovascular disease, but the functions of BCAA catabolism in platelets remain unknown. Methods: The activity of human platelets from healthy subjects before and after ingestion of BCAAs was measured. Protein phosphatase 2Cm specifically dephosphorylates branched-chain α-keto acid dehydrogenase and thereby activates BCAA catabolism. Protein phosphatase 2Cm–deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation. Results: We found that ingestion of BCAAs significantly promoted human platelet activity (n=5; P <0.001) and arterial thrombosis formation in mice (n=9; P <0.05). We also found that the valine catabolite α-ketoisovaleric acid and the ultimate oxidation product propionyl-coenzyme A showed the strongest promotion effects on platelet activation, suggesting that the valine/α-ketoisovaleric acid catabolic pathway plays a major role in BCAA-facilitated platelet activation. Protein phosphatase 2Cm deficiency significantly suppresses the activity of platelets in response to agonists (n=5; P <0.05). Our results also suggested that BCAA metabolic pathways may be involved in the integrin αIIbβ3–mediated bidirectional signaling pathway that regulates platelet activation. Mass spectrometry identification and immunoblotting revealed that BCAAs enhanced propionylation of tropomodulin-3 at K255 in platelets or Chinese hamster ovary cells expressing integrin αIIbβ3. The tropomodulin-3 K255A mutation abolished propionylation and attenuated the promotion effects of BCAAs on integrin-mediated cell spreading, suggesting that K255 propionylation of tropomodulin-3 is an important mechanism underlying integrin αIIbβ3–mediated BCAA-facilitated platelet activation and thrombosis formation. In addition, the increased levels of BCAAs and the expression of positive regulators of BCAA catabolism in platelets from patients with type 2 diabetes mellitus are significantly correlated with platelet hyperreactivity. Lowering dietary BCAA intake significantly reduced platelet activity in ob/ob mice (n=4; P <0.05). Conclusions: BCAA catabolism is an important regulator of platelet activation and is associated with arterial thrombosis risk. Targeting the BCAA catabolism pathway or lowering dietary BCAA intake may serve as a novel therapeutic strategy for metabolic syndrome–associated thrombophilia.

Identification of a Mathematical Model for the Prediction of Platelet Damage Accumulation in Artificial Organs: A Preliminary Study

2007 ◽  
Author(s):  
Matteo Nobili ◽  
Jawaad Sheriff ◽  
Umberto Morbiducci ◽  
Alberto Redaelli ◽  
Danny Bluestein
Keyword(s):  
Platelet Activation ◽  
Damage Accumulation ◽  
Heart Valves ◽  
Implantable Devices ◽  
Artificial Organs ◽  
Model Parameters ◽  
Reliable Technique ◽  
Prosthetic Devices ◽  
High Incidence ◽  
Preliminary Study

Platelets are the pre-eminent cell involved in hemostasis and thrombosis. In recent years it has been demonstrated that flow-induced platelet activation is a major cause for the relatively high incidence of thromboembolic complications in mechanical heart valves (MHVs) [1,2].The platelet activation state (PAS) assay has proved to be a reliable technique for the experimental measurement of procoagulant activity [3]. A Predictive numerical model for platelets damage accumulation could provide critical information for thrombogenicity optimization of implantable prosthetic devices. This would lead to improving the safety and efficacy of implantable devices. Reliable models able to predict this phenomenon are still lacking. The aim of this work is an attempt to bridge this gap. A model for describing the activation of formed elements in blood requires establishing a correlation between mechanical loading, exposure time and the phenomenological response of these elements to it. A physically consistent phenomenological model is used [4] and genetic algorithms (GAs) [5], have been successfully applied to the tuning of the model parameters by correlating its predictions to PAS measurements conducted in a Hemodynamic Shearing Device (HSD) by exposing platelets to prescribed shear stress loading waveforms.

scholarly journals Increased Pro-Thrombotic Platelet Activity Associated with Thrombin/PAR1-Dependent Pathway Disorder in Patients with Secondary Progressive Multiple Sclerosis

2020 ◽  
Vol 21 (20) ◽  
pp. 7722
Author(s):  
Angela Dziedzic ◽  
Elzbieta Miller ◽  
Michal Bijak ◽  
Lukasz Przyslo ◽  
Joanna Saluk-Bijak
Keyword(s):  
Multiple Sclerosis ◽  
Mrna Expression ◽  
Platelet Activation ◽  
Blood Platelets ◽  
Surface Expression ◽  
Epidemiological Studies ◽  
Progressive Multiple Sclerosis ◽  
Apolipoprotein A1 ◽  
Platelet Activity ◽  
Activation Markers

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.

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