Journal articles on the topic 'Platelet resistance'
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1
Uchiyama, Satoshi, Josh Sun, Kyoko Fukahori, Nao Ando, Mengyou Wu, Flavio Schwarz, Shoib S. Siddiqui, Ajit Varki, Jamey D. Marth, and Victor Nizet. "Dual actions of group BStreptococcuscapsular sialic acid provide resistance to platelet-mediated antimicrobial killing." Proceedings of the National Academy of Sciences 116, no. 15 (March 25, 2019): 7465–70. http://dx.doi.org/10.1073/pnas.1815572116.
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Circulating platelets have important functions in thrombosis and in modulating immune and inflammatory responses. However, the role of platelets in innate immunity to bacterial infection is largely unexplored. While human platelets rapidly killStaphylococcus aureus, we found the neonatal pathogen group BStreptococcus(GBS) to be remarkably resistant to platelet killing. GBS possesses a capsule polysaccharide (CPS) with terminal α2,3-linked sialic acid (Sia) residues that mimic a common epitope present on the human cell surface glycocalyx. A GBS mutant deficient in CPS Sia was more efficiently killed by human platelets, thrombin-activated platelet releasate, and synthetic platelet-associated antimicrobial peptides. GBS Sia is known to bind inhibitory Sia-recognizing Ig superfamily lectins (Siglecs) to block neutrophil and macrophage activation. We show that human platelets also express high levels of inhibitory Siglec-9 on their surface, and that GBS can engage this receptor in a Sia-dependent manner to suppress platelet activation. In a mouse i.v. infection model, antibody-mediated platelet depletion increased susceptibility to platelet-sensitiveS. aureusbut did not alter susceptibility to platelet-resistant GBS. Elimination of murine inhibitory Siglec-E partially reversed platelet suppression in response to GBS infection. We conclude that GBS Sia has dual roles in counteracting platelet antimicrobial immunity: conferring intrinsic resistance to platelet-derived antimicrobial components and inhibiting platelet activation through engagement of inhibitory Siglecs. We report a bacterial virulence factor for evasion of platelet-mediated innate immunity.
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Bergmeier, Wolfgang, David S. Paul, Lucia Stefanini, Raymond F. Robledo, E. Ricky Chan, Todd M. Getz, Raymond Piatt, Yacine Boulaftali, Mark D. Adams, and Luanne L. Peters. "Premature Platelet Activation and Resistance to P2Y12 Inhibitors in Rasa3 Mutant Mice." Blood 124, no. 21 (December 6, 2014): 91. http://dx.doi.org/10.1182/blood.v124.21.91.91.
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Abstract The small GTPase RAP1 is critical for platelet activation and thrombus formation. RAP1 activity in platelets is controlled by the guanine nucleotide exchange factor CalDAG-GEFI and an unknown regulator operating downstream of the ADP receptor, P2Y12, the target of antithrombotic therapy. Here we provide evidence that the GTPase-activating protein, RASA3, is a critical inhibitor of platelet activation and the missing link in the P2Y12/RAP1 signaling pathway. Genetic inactivation of Rasa3 led to premature activation and markedly reduced lifespan of circulating platelets in mice (t1/2=14 hrs vs. 55 hrs in controls). The increased platelet turnover and the resulting thrombocytopenia were reversed by concomitant deletion of CalDAG-GEFI. Rasa3 mutant platelets were hyperresponsive to agonist stimulation, both in vitro and in vivo. Importantly, activation of Rasa3 mutant platelets occurred independently of ADP feedback signaling and was insensitive to inhibitors of P2Y12 or PI3 kinase. Thus, constitutively active RASA3 ensures that circulating platelets remain quiescent by restraining CalDAG-GEFI/RAP1 signaling. At sites of vascular injury, P2Y12 signaling is required to inhibit RASA3 and enable sustained RAP1-dependent platelet activation and thrombus formation. Our findings provide critical mechanistic insights for the antithrombotic effect of P2Y12 inhibitors and may lead to improved diagnosis and treatment of platelet-related disorders. Disclosures No relevant conflicts of interest to declare.
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Kahn, Nighat, Bilal Khan, and Asru K. Sinha. "Resistance of Platelets in Hypercholesterolemia to Inhibition by Activated Coagulation Factor X." ISRN Vascular Medicine 2011 (November 30, 2011): 1–6. http://dx.doi.org/10.5402/2011/165018.
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Platelet hyperactivity may be involved in the pathogenesis of both thrombogenesis and hypercholesterolemia. The cholesterol-enriched states may contribute to accelerated development of atherosclerosis. The effect of high cholesterol on platelet activation and on inhibition by coagulation factor Xa, was studied in vitro. Incubation of normal platelets (n=20) with cholesterol-rich dispersion resulted in a small increase of platelet aggregation (PA) and thromboxane A2 (TXA2) synthesis when compared with platelets incubated with cholesterol-normal dispersion. In hypercholesterolemic patients (n=20), ADP-induced PA and TXA2 synthesis showed only small increases over normal controls. Addition of factor Xa (1 unit/mL) prevented the ADP-induced PA and markedly inhibited TXA2 synthesis in normal platelets (1.3±0.2 and 8.7±2.0 pmol TXA2/108 platelets, with and without factor Xa, resp.). However, factor Xa failed to significantly suppress TXA2 synthesis in cholesterol-incubated normal platelets (9.5±1.4 and 11.8±1.3 pmol TXA2/108 platelets, with and without factor Xa; resp., P=NS) as well as in platelets from patients with hypercholesterolemia (8.6±4.0 and 10.9±4.9 pmol TXA2/108 platelets, with and without factor Xa; resp., P=NS). Exposure of platelets to high cholesterol concentrations, in vitro and in vivo, marginally increased PA and TXA2 synthesis but resulted in loss of responsiveness to factor Xa, which could significantly contribute to platelet activation in hypercholesterolemic states.
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Taube, Janis, Nicola McWilliam, Roger Luddington, Christopher D. Byrne, and Trevor Baglin. "Activated Protein C Resistance: Effect of Platelet Activation, Platelet-Derived Microparticles, and Atherogenic Lipoproteins." Blood 93, no. 11 (June 1, 1999): 3792–97. http://dx.doi.org/10.1182/blood.v93.11.3792.
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Abstract Plasma and platelet factor Va represent different substrates for activated protein C (APC). In this study, we have measured platelet-dependent APC resistance and the effect of aspirin and a platelet glycoprotein IIbIIIa antagonist (GR144053F) on this phenomenon. In platelet rich plasma (PRP), progressive APC resistance was observed with increasing platelet activation. APC sensitivity ratios of 1.8, 1.7, and 1.4 were observed after platelet activation with thrombin receptor activating peptide (TRAP), collagen, and A23187, respectively. Ultracentrifugation at 77,000g for 1 hour abolished APC resistance indicating that the phenotype is associated exclusively with the platelet membrane. APC resistance was not observed in the presence of phosphatidylcholine-phosphatidylserine (PCPS) vesicles or purified human plasma lipoproteins. APC resistance was observed in the presence of platelet-derived microparticles, but to a lesser degree than that in the presence of activated platelets. The platelet-dependent APC resistance phenotype was also observed when endogenous APC was generated by Protac (American Diagnostica, Inc, Greenwich, CT). In vitro inhibition of platelet activation with aspirin had no effect, but the fibrinogen receptor antagonist, GR144053F, inhibited platelet-dependent APC resistance. These results indicate that platelet activation results in an APC-resistant phenotype comparable to that observed in the plasma of patients with factor V gene mutations affecting critical APC cleavage sites. This suggests that platelet activation at the site of endothelial damage downregulates a critical natural anticoagulant mechanism. The antithrombotic effect of aspirin may be due to an indirect effect on platelet-dependent APC resistance with reduced platelet retention within a developing thrombus. The more potent antithrombotic effect of glycoprotein IIbIIIa antagonists may in addition be the result of reduced platelet factor Va expression and modulation of the platelet-dependent APC resistance phenotype.
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Taube, Janis, Nicola McWilliam, Roger Luddington, Christopher D. Byrne, and Trevor Baglin. "Activated Protein C Resistance: Effect of Platelet Activation, Platelet-Derived Microparticles, and Atherogenic Lipoproteins." Blood 93, no. 11 (June 1, 1999): 3792–97. http://dx.doi.org/10.1182/blood.v93.11.3792.411k06_3792_3797.
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Plasma and platelet factor Va represent different substrates for activated protein C (APC). In this study, we have measured platelet-dependent APC resistance and the effect of aspirin and a platelet glycoprotein IIbIIIa antagonist (GR144053F) on this phenomenon. In platelet rich plasma (PRP), progressive APC resistance was observed with increasing platelet activation. APC sensitivity ratios of 1.8, 1.7, and 1.4 were observed after platelet activation with thrombin receptor activating peptide (TRAP), collagen, and A23187, respectively. Ultracentrifugation at 77,000g for 1 hour abolished APC resistance indicating that the phenotype is associated exclusively with the platelet membrane. APC resistance was not observed in the presence of phosphatidylcholine-phosphatidylserine (PCPS) vesicles or purified human plasma lipoproteins. APC resistance was observed in the presence of platelet-derived microparticles, but to a lesser degree than that in the presence of activated platelets. The platelet-dependent APC resistance phenotype was also observed when endogenous APC was generated by Protac (American Diagnostica, Inc, Greenwich, CT). In vitro inhibition of platelet activation with aspirin had no effect, but the fibrinogen receptor antagonist, GR144053F, inhibited platelet-dependent APC resistance. These results indicate that platelet activation results in an APC-resistant phenotype comparable to that observed in the plasma of patients with factor V gene mutations affecting critical APC cleavage sites. This suggests that platelet activation at the site of endothelial damage downregulates a critical natural anticoagulant mechanism. The antithrombotic effect of aspirin may be due to an indirect effect on platelet-dependent APC resistance with reduced platelet retention within a developing thrombus. The more potent antithrombotic effect of glycoprotein IIbIIIa antagonists may in addition be the result of reduced platelet factor Va expression and modulation of the platelet-dependent APC resistance phenotype.
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Reed, Guy L., Gary R. Matsueda, and Edgar Haber. "Platelet Factor XIII Increases the Fibrinolytic Resistance of Platelet-Rich Clots by Accelerating the Crosslinking of α2-Antiplasmin to Fibrin." Thrombosis and Haemostasis 68, no. 03 (1992): 315–20. http://dx.doi.org/10.1055/s-0038-1656372.
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SummaryPlatelet clots resist fibrinolysis by plasminogen activators. We hypothesized that platelet factor XIII may enhance the fibrinolytic resistance of platelet-rich clots by catalyzing the crosslinking of α2-antiplasmin (α2AP) to fibrin. Analysis of plasma clot structure by polyacrylamide gel electrophoresis and immunoblotting revealed accelerated α2AP-fibrin crosslinking in platelet-rich compared with platelet-depleted plasma clots. A similar study of clots formed with purified fibrinogen (depleted of factor XIII activity), isolated platelets, and specific factor XIII inhibitors indicated that this accelerated crosslinking was due to the catalytic activity of platelet factor XIII. Moreover, when washed platelets were aggregated by thrombin, there was evidence of platelet factor XIII-mediated crosslinking between platelet α2AP and platelet fibrin(ogen). Specific inhibition (by a monoclonal antibody) of the α2AP associated with washed platelet aggregates accelerated the fibrinolysis of the platelet aggregate. Thus in platelet-rich plasma clots, and in thrombin-induced platelet aggregates, platelet factor XIII actively formed α2AP-fibrin crosslinks, which appeared to enhance the resistance of platelet-rich clots to fibrinolysis.
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Schwartz, Kenneth A., Dianne E. Schwartz, Kimberly Barber, Mathew Reeves, and Anthony C. DeFranco. "Minimal Frequency of Aspirin Resistance after Observed Aspirin Ingestion." Blood 106, no. 11 (November 16, 2005): 551. http://dx.doi.org/10.1182/blood.v106.11.551.551.
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Abstract Poor compliance is an important cause of aspirin resistance. Our goal was to investigate amount of aspirin induced inhibition of platelets independent of compliance. We investigated the net amount of aspirin induced inhibition of platelets by comparing Platelet Prostaglandin Agonist (PPA) stimulated platelet aggregations before, off aspirin, with the platelet inhibition that occurred 2 hours after observed aspirin ingestion. 217 post-myocardial infarction patients who had taken aspirin for at least 30 days were evaluated at two time points. The first time point was 7 days after they had signed informed consent to stop taking aspirin as well as nonsteroidal anti-inflammatory drugs (NSAIDs). The second time point was 2 hrs after they were observed to ingest 325mg of aspirin. Platelets were evaluated using 2 different agonists in a light aggregometer. Arachidonic acid (AA) was used as a qualitative check to see if the patients at the first time point had really refrained from taking aspirin and NSAIDs for 7 days and PPA which mainly activates platelets via the prostaglandin pathway and can detect degrees of aspirin induced platelet inhibition. The slope of the PPA stimulated aggregation curve was used to measure aspirin induced platelet inhibition. The net aspirin response was calculated by determining the paired difference between the PPA slopes at the two time points. Compliance with the directive of not taking aspirin or NSAIDs before the first time point was checked with AA stimulated aggregometry and 45 patients were judged to be noncompliant. We defined aspirin resistance as a minimal change in PPA slope of 15 or less. Of the patients who had complied with the directive not to take aspirin or NSAIDs for 7 days as determined by AA aggregometry only 7 (3.2%) were aspirin resistant. The net aspirin response was directly related to the PPA slope off aspirin (p<0.001). When the 45 patients who were judged by AA aggregometry to be noncompliant with the directive to refrain from taking aspirin or NSAIDs were removed from the analysis, the direct relationship between the slope of the off aspirin PPA aggregation and the net aspirin response remained significant (p<0.001). The amount of platelet inhibition in the compliant group 42±16 was significantly larger than the platelet inhibition in the noncompliant group 36±16 (p=0.02). We conclude that: 1. a small percent of patients, 3.2%, whose net amount of aspirin induced platelet inhibition was less than 15 may be resistant to aspirin because of mechanisms unrelated to compliance and 2. The net amount of aspirin induced inhibition of platelets is directly related to the slope of the “off” aspirin PPA stimulated aggregation curve.
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Stegnar, Mojca. "Platelet function tests and resistance to antiplatelet therapy." Srpski arhiv za celokupno lekarstvo 138, suppl. 1 (2010): 59–63. http://dx.doi.org/10.2298/sarh10s1059s.
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The clinical efficacy of antiplatelet therapy (aspirin, P2Y12 and glycoprotein IIb/IIIa receptor antagonists) to prevent occlusive arterial events in patients with atherothrombotic disease is well established. Despite the proven benefits of antiplatelet therapy, many patients continue to experience arterial events. Many factors may influence the response of platelets to antiplatelet therapy and some patients with adequate compliance to the treatment may exhibit failure of platelet inhibition as determined by ex vivo laboratory tests, a phenomenon termed ?resistance?to antiplatelet therapy. Platelet function can be measured by numerous platelet function tests, with which various parameters of platelet activation, secretion, adhesion and aggregation can be determined. These tests include light transmission (optical) and whole blood aggregometry, point-of-care devices, such as platelet function analyzers PFA-100?, and VerifyNow?, flow cytometry, serum thromboxane B2 and urinary levels of the thromboxane B2 metabolite 11-dehyro-thromboxane B2. Other tests, such as whole blood platelet aggregation measured by platelet counting, thrombelastography and devices such as the cone and plate(let) analyzer, Plateletworks and thrombotic status analyzer have also been used to determine platelet inhibition by antiplatelet drugs, but their use is not widespread and therefore experience is limited. Further studies need to be carried out to answer basic questions on the clinical utility and cost-effectiveness of laboratory monitoring of antiplatelet therapy before it can be recommended in clinical practice.
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Alemanno, Laura, Isabella Massimi, Vanessa Klaus, Maria Guarino, Teresa Maltese, Luigi Frati, Dominick Angiolillo, and Fabio Pulcinelli. "Impact of Multidrug Resistance Protein-4 Inhibitors on Modulating Platelet Function and High on-Aspirin Treatment Platelet Reactivity." Thrombosis and Haemostasis 118, no. 03 (February 15, 2018): 490–501. http://dx.doi.org/10.1055/s-0038-1629920.
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AbstractPlatelet multidrug resistance protein 4 (MRP4) plays a modulating role on platelet activation. Platelet function and thrombus formation are impaired in MRP4 knockout mice models, and, among aspirin-treated patients, high on-aspirin residual platelet reactivity (HARPR) positively correlates with MRP4 levels. To better understand the effects of MRP4 on platelet function, the aim of this investigation was to assess the impact of cilostazol-induced inhibition of MRP4-mediated transport and assess aspirin-induced antiplatelet effects and rates of HARPR in human subjects.Cilostazol-dependent inhibition of MRP4-mediated transport was assessed with the release of the fluorescent adduct bimane-glutathione and aspirin entrapment. Effect of Cilostazol on cAMP inhibition was evaluated by vasodilator-stimulated phosphoprotein (VASP). Platelet function was studied by collagen and TRAP-6-induced platelet aggregation and secretion.Cilostazol reduced the release of bimane-glutathione and enhanced aspirin entrapment demonstrating an inhibitory effect on MRP4 in platelets. VASP phosphorylation was absent until 10 seconds after addition of cilostazol, and becomes evident after 30 seconds. An inhibitory effect on platelet aggregation and secretion was found in activated platelets, with threshold concentration of agonists, 10 seconds after addition of cilostazol, supporting a role of MRP4 on platelet function that is cAMP independent. Cilostazol effects were also shown in aspirin-treated platelets. A reduction of platelet aggregation and secretion were observed in aspirin-treated patients with HARPR.This study supports the role of MRP4 on modulating platelet function which occurs through cAMP-independent mechanisms. Moreover, inhibition of MRP4 induced by cilostazol enhances aspirin-induced antiplatelet effects and reduces HARPR.
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Chen, Hung Yi, and Pesus Chou. "Associations Between PFA-Measured Aspirin Resistance, Platelet Count, Renal Function, and Angiotensin Receptor Blockers." Clinical and Applied Thrombosis/Hemostasis 24, no. 9_suppl (July 11, 2018): 63S—68S. http://dx.doi.org/10.1177/1076029618786588.
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Aspirin resistance is used to describe patients who are undergoing aspirin therapy but fail for the inhibition of thromboxane biosynthesis in platelets. Although the true mechanism is unclear, drug–drug interaction remains a possible factor. The study aimed to determine whether there was association between aspirin resistance and the concomitant cardiovascular medication. Using the Platelet Function Analyzer-100 system, aspirin resistance was evaluated in aspirin-treated patients from the outpatient department. The associations between aspirin resistance and their concomitant common cardiovascular medication were analyzed. Aspirin resistance was prevalent in 147 (17.7%) of 831 patients. Concomitant angiotensin receptor blocker (ARB) treatment and low platelet count were associated with aspirin response ( P = .04, .02, respectively). Multivariate logistic regression analysis results showed an association between aspirin response and ARB therapy (adjusted odds ratio [OR] 1.48; 95% confidence interval, CI: 1.08-2.18). And the association was blunted when platelet count was considered (adjusted OR 1.43, 95% CI: 0.92-2.23). In ARB-treated patients, increased creatinine and decreased hematocrit laboratory data increased the risk of aspirin resistance ( P = .02, .04, respectively), and the effect of platelet count on aspirin resistance was diminished by ARB therapy. Concomitant ARB treatment in aspirin-treated patients decreased the risk of aspirin resistance, and the effect was dependent on low platelet count. In ARB-treated patients, increased creatinine and decreased hematocrit data increased the risk of aspirin resistance. In addition, the effect of platelet count on aspirin resistance was diminished by ARB treatment.
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Klamroth, Robert, Stefan Hoffmann, Dietrich Andresen, and Helmut Landgraf. "Clopidogrel Resistance and Aspirin Resistance - a Cause of Coronary Artery Stent Thrombosis?." Blood 104, no. 11 (November 16, 2004): 4070. http://dx.doi.org/10.1182/blood.v104.11.4070.4070.
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Abstract Background: Occlusions of coronary artery stents are a seldom but often fatal complication after coronary artery intervention. With aggressive platelet inhibition therapy (combination of Aspirin (ASS) and clopidogrel) a reduction of stent thrombosis to less than 2% was achieved. The inhibition of platelet function has great interindividual variability and resistance against ASS and/or clopidogrel were previously described. Therefore we studied the relation between coronary artery stent thrombosis and insufficient inhibition of platelet function in patients after coronary artery intervention. Methods: Between 2000 and 2003 we examined 20 patients (pts) with coronary artery stent thrombosis within 4 weeks after coronary artery intervention. All patients received a clopidogrel loading dose of 300mg followed by 75mg/die and ASS 100mg/die. Platelet inhibition was studied by light transmittance aggregometry in platelet rich plasma (Aggregometer PAP 4, moelab inc.). Aggregation was recorded as the maximum percentage change in light transmittance from baseline using platelet poor plasma as a reference. We defined ASS resistance as platelet aggregation > 30% after induction with 0,5mg/ml arachidonic acid and clopidogrel resistance as platelet aggregation > 30% after induction with 20 μmol ADP. We compared these pts with 20 pts without stent thrombosis within 4 weeks after coronary artery intervention. Results: In the group with coronary artery stent thrombosis we found 13/20 patients with insufficient platelet inhibition. 2/20 pts in this group were resistent against both ASS and clopidogrel. In 2/20 pts we observed ASS resistance and in 9/20 pts clopidgrel resistance. In the group of patients without stent thrombosis we found only 1/20 pt with ASS resistance and 1/20 pt with clopidogrel resistance. Conclusions: Insufficient platelet inhibition could be one cause of early stent thrombosis after coronory artery intervention. Platelet function testing is able to detect insufficient platelet inhibition and early testing could be an instrument to prevent coronary artery stent thrombosis.
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Goncharov, M. D., Yu I. Grinshtein, and A. A. Savchenko. "Features of the reactive oxygen species production by platelets and neutrophils in the formation of an insufficient response to acetylsalicylic acid in patients with coronary heart disease after coronary bypass surgery." Translational Medicine 9, no. 1 (April 15, 2022): 12–28. http://dx.doi.org/10.18705/2311-449-2022-9-1-12-28.
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Background. Aspirin resistance can lead to thrombosis. Platelets interact with neutrophils in the focus of atherosclerotic damage. The levels of synthesis of reactive oxygen species (ROS) characterize their functional potential. Platelet resistance to acetylsalicylic acid (ASA) can affect the synthesis of ROS.Objective. To reveal the features of ROS synthesis by platelets and neutrophils in patients with coronary heart disease (CHD) after coronary artery bypass grafting (CABG) depending on sensitivity to ASA and antiplatelet therapy.Design and methods. There were 104 patients with CHD and 36 healthy donors. Patients stopped receiving antiplatelet agents 5 days before CABG, ASA was prescribed after surgery, patients on dual antiplatelet therapy (DAT) clopidogrel were added to ASA for 2–3 days. Resistance to ASA was determined at a level of platelet aggregation with arachidonic acid ≥ 20 %. The ROS synthesis levels were examined by the chemiluminescent method (CL).Results. 31.7 % of patients were resistant to ASA (rASA). In ASA-sensitive patients (sASA), CL values were increased. In rASA on DAT, CL parameters were increased, but did not differ from sASA. In the sASA and rASA groups on ASA therapy, correlations between neutrophil and platelet CL parameters were revealed.Conclusion. The presence or absence of interaction between platelets and neutrophils at the level of receptors and/or microvesicles can lead to platelet resistance to ASA in patients with coronary artery disease. Sometimes, this effect could be compensated by DAT.
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Mitchell, W. Beau, Michele N. Edison, Mariana P. Pinheiro, Nayla Boulad, Bethan Psaila, Marissa Karpoff, Kaplan David, et al. "The Effect of Eltrombopag on Platelet Resistance to Apoptosis: The Role of the Bcl-Xl Pathway." Blood 118, no. 21 (November 18, 2011): 1158. http://dx.doi.org/10.1182/blood.v118.21.1158.1158.
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Abstract Abstract 1158 INTRODUCTION: Immune thrombocytopenia (ITP) is typically characterized by increased platelet destruction and reduced platelet production. Eltrombopag and Romiplostim are thrombopoietin receptor (TPO-R) agonists that are known to increase platelet counts in patients with ITP by stimulating thrombopoiesis. Platelets also express TPO-R on their surface, but it is unknown whether the thrombopoietin mimetics (TPO-M) have a direct effect on the circulating platelets. Although controversial, in a very small number of ITP patients, TPO-M agents may increase platelet counts in 2–5 days, earlier than would be expected from de novo megakaryocytopoiesis. Platelet survival is hypothesized to be mediated by two molecular intermediates in an apoptotic pathway, Bcl-xL and Bak. Bcl-xL/Bak protein expression in megakaryocytes is regulated in part by TPO-mediated activation of Akt pathways through Jak2 and Stat5. We hypothesized that an increase in platelet count in the first week of treatment might be mediated by TPO-R signaling, resulting in decreased platelet apoptosis. This study explored whether Eltrombopag or Romiplostim treatment has anti-apoptotic effects on platelets of patients with ITP. METHODS: Following a treatment wash out period, 75 mg of Eltrombopag once daily or 10 mcg/kg weekly of Romiplostim was initiated for 2 weeks. Blood counts were measured on days 1, 3, 5, 8, 10, 12, and 15. Platelet function and survival was assessed on days 1, 8, and 15 by: immature platelet fraction (IPF), glycocalicin index, Bcl-xL inhibitor (ABT-737) assay, measurement of Bcl-xL by western blot, measurement of several members of the Bcl-xL Akt mediated, apoptotic pathway by flow cytometry (FACS), bleeding score, measurement of thrombin-anti-thrombin complexes (TATs), and quantification of microparticles. RESULTS: Eight of 10 patients responded to treatment with Eltrombopag with a platelet count ≥ 50,000/μL, and 6 of the 8 responders at least doubled their counts during the 2 weeks of treatment. All 3 patients treated with Romiplostim responded with platelet count ≥ 50,000/μL. In both treatment groups there was a significant increase in median platelet count (p<0.001), median large platelet count (p<0.01), and median absolute IPF (A-IPF, p<0.01), while there was no significant change in median % IPF. The dose of ABT-737 required to kill half of the platelets in the sample (IC50) in the Eltrombopag group was lower in patients at day 1 than in non-ITP controls, and there was an increase in resistance to apoptosis between days 1 and 8, but these changes did not reach statistical significance. Between days 8 and 15 the IC50 declined to pre-treatment levels. In the Romiplostim group there was no significant difference in IC50 between the control and the patients over the 2 weeks of study. There was no significant correlation between the platelet counts and the IC50 values. FACS analysis of members of the AKT signal transduction pathway revealed increased activation of each of the markers between days 1 and 8, followed by a decrease between days 8 and 15. The levels of Bcl-xL and phosphor-AKT(308) decreased from day 1 to day 15. The other lab tests are pending. DISCUSSION: Because the A-IPF increased by less than the platelet increase and because the lifespan of the A-IPF is not known, it is unclear if the platelet count increase is solely a result of increased platelet production. Platelet lifespan may be enhanced by Eltrombopag treatment as there was a parallel albeit transient increase in AKT activation markers and platelet apoptosis resistance in the Eltrombopag group. Treatment with Romiplostim did not appear to affect apoptosis resistance although it did result in transient AKT activation. Our data suggest that platelets are more resistant to apoptosis when the levels of anti-apoptotic factors (eg. PTEN, Phospho-GSK3β) involved in the AKT/Bcl-xL pathway are greatest despite a concomitant increase in pro-apoptotic factors (eg. Bak, Bax). Since both the increased AKT activation and apoptotic resistance returned to baseline at day 15, megakaryocytes and platelets already present at the start of treatment may respond differently than those generated de novo in the presence of TPO mimetics. Disclosures: Bussel: Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding.
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Massarelli, Laura, Giuseppe Musumeci, Carlo Bussolino, and Valerio Tomaselli. "Diabetes mellitus and clopidogrel “resistance”." Clinical Management Issues 5, no. 2S (October 13, 2015): 55–58. http://dx.doi.org/10.7175/cmi.v5i2s.1112.
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In our Department arrives a 75-year-old patient with hypertension, diabetes mellitus (DM) treated with hypoglycaemic drugs, dyslipidaemia and ischaemic heart disease post-acute myocardial infarction treated with triple coronary artery bypass surgery and subsequent percutaneous transluminal coronary angioplasty (PTCA). After a new PTCA and positioning of medical stent he is discharged with a double antiplatelet therapy. But after one month two thrombotic events occur in this patients almost simultaneously. Antiplatelet therapy such as clopidogrel and aspirin in combination, is the current gold standard for reducing cardiovascular events in patients with DM, providing a synergistic platelet inhibition through different platelet activation pathways, but platelets of DM patients are characterised by disregulation of several signalling pathways which may play a role not only in the higher risk of developing cardiovascular events and the worse outcome, but also in the larger proportion of DM patients with inadequate response to antiplatelet drugs compared to non DM subjects.
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Braaten, JV, WG Jerome, and RR Hantgan. "Uncoupling fibrin from integrin receptors hastens fibrinolysis at the platelet-fibrin interface." Blood 83, no. 4 (February 15, 1994): 982–93. http://dx.doi.org/10.1182/blood.v83.4.982.982.
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Abstract A well-characterized in vitro model system composed of thrombin- stimulated gel-filtered human platelets, fibrin-(ogen), plasminogen, and recombinant tissue plasminogen activator (rt-PA) was used to examine the relationship between platelet-fibrin adhesive interactions and the lytic resistance of a platelet-rich thrombus. Laser light scattering kinetic experiments demonstrated that the ligand-mimetic peptide D-RGDW and an anti-alpha IIb beta 3 monoclonal antibody both inhibited clot retraction, but neither integrin-targeted reagent affected the overall delay in lysis of “bulk” fibrin caused by thrombin- stimulated platelets. However, lysis of the model platelet-rich thrombus did proceed some 30% more quickly when treated with a plasminogen activator inhibitor (PAI)-resistant t-PA variant. Taken together, these results confirm that platelet-released PAI-1 is a major determinant of global lytic resistance. Next events occurring during fibrinolysis in the unique microenvironment near the platelet surface were monitored by scanning electron microscopy and quantitative fluorescence microscopy. Scanning electron micrographs of the partially lysed model thrombus in the presence of 200 mumol/L of D-RGDW showed no platelet aggregates, and fibrin was attached by fewer strands to the platelets. Quantitative fluorescence microscopy, using fluorescein- labeled fibrin, showed that fibrin adherent to the surface of thrombin- stimulated platelets lysed 20% to 50% more slowly than bulk fibrin (monitored in parallel by laser light scattering). Furthermore, this microspectroscopic technique showed that D-RGDW reduced the quantity of platelet-bound fibrin, and accelerated lysis near the platelet surface with both native rt-PA and the PAI-resistant variant. These observations suggest that the dense network of fibrin bound to the platelet surface is protected from fibrinolysis by tissue-type plasminogen activators. Further, uncoupling fibrin from its platelet receptors uniquely hastens fibrinolysis at the cell/fibrin interface.
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Braaten, JV, WG Jerome, and RR Hantgan. "Uncoupling fibrin from integrin receptors hastens fibrinolysis at the platelet-fibrin interface." Blood 83, no. 4 (February 15, 1994): 982–93. http://dx.doi.org/10.1182/blood.v83.4.982.bloodjournal834982.
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A well-characterized in vitro model system composed of thrombin- stimulated gel-filtered human platelets, fibrin-(ogen), plasminogen, and recombinant tissue plasminogen activator (rt-PA) was used to examine the relationship between platelet-fibrin adhesive interactions and the lytic resistance of a platelet-rich thrombus. Laser light scattering kinetic experiments demonstrated that the ligand-mimetic peptide D-RGDW and an anti-alpha IIb beta 3 monoclonal antibody both inhibited clot retraction, but neither integrin-targeted reagent affected the overall delay in lysis of “bulk” fibrin caused by thrombin- stimulated platelets. However, lysis of the model platelet-rich thrombus did proceed some 30% more quickly when treated with a plasminogen activator inhibitor (PAI)-resistant t-PA variant. Taken together, these results confirm that platelet-released PAI-1 is a major determinant of global lytic resistance. Next events occurring during fibrinolysis in the unique microenvironment near the platelet surface were monitored by scanning electron microscopy and quantitative fluorescence microscopy. Scanning electron micrographs of the partially lysed model thrombus in the presence of 200 mumol/L of D-RGDW showed no platelet aggregates, and fibrin was attached by fewer strands to the platelets. Quantitative fluorescence microscopy, using fluorescein- labeled fibrin, showed that fibrin adherent to the surface of thrombin- stimulated platelets lysed 20% to 50% more slowly than bulk fibrin (monitored in parallel by laser light scattering). Furthermore, this microspectroscopic technique showed that D-RGDW reduced the quantity of platelet-bound fibrin, and accelerated lysis near the platelet surface with both native rt-PA and the PAI-resistant variant. These observations suggest that the dense network of fibrin bound to the platelet surface is protected from fibrinolysis by tissue-type plasminogen activators. Further, uncoupling fibrin from its platelet receptors uniquely hastens fibrinolysis at the cell/fibrin interface.
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Kumar, Ashwani, and John Kao. "Platelet Resistance to Antiplatelet Drugs." Recent Patents on Cardiovascular Drug Discovery 4, no. 2 (June 1, 2009): 98–108. http://dx.doi.org/10.2174/157489009788452959.
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Cattaneo, Marco. "Resistance to anti-platelet agents." Thrombosis Research 127 (February 2011): S61—S63. http://dx.doi.org/10.1016/s0049-3848(11)70017-2.
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Fumelli, Paolo, Rosa Anna Rabini, Roberto Testa, Roberto Staffolani, Daniele Fumelli, Natalia Moretti, Simonetta Serra, and Laura Mazzanti. "Platelet membranes and insulin resistance." Diabetes Research and Clinical Practice 50 (September 2000): 376. http://dx.doi.org/10.1016/s0168-8227(00)81285-1.
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Mitchell, W. Beau, Michele N. Edison, Mariana P. Pinheiro, Nayla Boulad, Bethan Psaila, Marissa Karpoff, David Kaplan, et al. "The Effect of Eltrombopag on Human Platelet Resistance to Apoptosis: The Role of the Bcl-Xl Pathway." Blood 116, no. 21 (November 19, 2010): 2520. http://dx.doi.org/10.1182/blood.v116.21.2520.2520.
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Abstract Abstract 2520 Introduction: Immune thrombocytopenia (ITP) is typically characterized by increased platelet destruction and reduced platelet production. Eltrombopag is a thrombopoietin receptor (TPO-R) agonist that is known to increase platelet counts in patients with ITP by stimulating thrombopoiesis, but it is unknown whether it has any effect on platelet life span. Platelet survival is mediated by two molecular intermediates in an apoptotic pathway, Bcl-xL and Bak. Bcl-xL protein expression in megakaryocytes is thought to be regulated in part by TPO-mediated activation of Akt pathways through Jak2 and Stat5. Although controversial, in a very small number of ITP patients, Eltrombopag may increase platelet counts in 2–5 days. We hypothesized that any increase in platelet count in the first week of treatment might be due to effects of Eltrombopag on platelet survival. Therefore, this study explored whether Eltrombopag treatment has anti-apoptotic effects in patients with ITP. Methods: Following a treatment wash out period, 75 mg of Eltrombopag once daily was initiated for 2 weeks. Blood counts were measured on days 1, 3, 5, 8, 10, 12, and 15. Platelet function and survival was assessed on days 1, 8, and 15 by: immature platelet fraction (IPF); glycocalicin index; Bcl-xL inhibitor (ABT-737) IC50, a novel assay adapted for human platelets; measurement of Bcl-xL by western blot; measurement of several members of the Bcl-xL Akt mediated, apoptotic pathway by flow cytometry (FACS); bleeding score; measurement of thrombin-anti-thrombin complexes (TATs); and quantification of microparticles. Results: Seven of the 9 patients responded to treatment with Eltrombopag with a platelet count ≥ 50,000/μL, and 6 of the 7 responders at least doubled their counts during the 2 weeks of treatment. There was a significant increase in median platelet count (p<0.001), median large platelet count (p<0.01), and median absolute IPF (A-IPF, p<0.01), while there was a significant decrease in median % IPF (p<0.05). The dose of ABT-737 required to kill half of the platelets in the sample (IC50) did not differ significantly between patients or between patients and controls during the first two weeks of treatment, and remained stable over the 2 weeks of study. However, the relative IC50 values (% of day 1 IC50 value) increased after the first week of treatment but returned to baseline after the second week. While these changes were not significant, their kinetics were similar to those seen in the AKT/ Bcl-xL signal transduction pathway (Figure). There was no significant correlation between the platelet counts and the IC50 values. FACS analysis of members of the AKT signal transduction pathway revealed significant increase in each of the markers between days 1 and 8 (p<0.01), followed by a significant decrease between days 8 and 15 (p<0.05), with no difference between days 1 and 15 (Figure). The other lab tests are pending. Discussion: Because the A-IPF increased by less than the platelet increase and because the life span of the A-IPF is not known, it is unclear if the overall platelet count increase is entirely a result of increased platelet production. Platelet life span may be enhanced by Eltrombopag treatment as there was a parallel albeit transient increase in AKT activation markers and platelet apoptosis resistance. Our data suggest that platelets are more resistant to apoptosis when the levels of anti-apoptotic factors (eg. PTEN, Phospho-GSK3β) involved in the AKT/Bcl-xL pathway are greatest despite a concomitant increase in pro-apoptotic factors (eg. Bak, Bax). Since both increased AKT activation and apoptotic resistance returned to baseline at day 15, megakaryocytes and platelets already present at the start of treatment may respond differently than those generated de novo in the presence of Eltrombopag. Disclosures: No relevant conflicts of interest to declare.
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Nickavar, Azar, Sahar Sadr Moharerpour, and Ehsan Abiry. "Predictive value of platelet indices in children with idiopathic nephrotic syndrome." Immunopathologia Persa 6, no. 1 (December 16, 2019): e04-e04. http://dx.doi.org/10.15171/ipp.2020.04.
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Introduction: Different biomarkers have been investigated for prognosis of patients with nephrotic syndrome. Qualitative and quantitative changes have been reported in platelets in these patients. Objectives: The aim of this study was to identify platelet abnormalities and their prognostic value of steroid response in children with idiopathic nephrotic syndrome. Patients and Methods: Platelet counts and indices (mean platelet volume [MPV], platelet distribution width [PDW] and platelet larger cell ratio [PLCR]) were evaluated and compared in 122 children with active nephrotic syndrome (64%; steroid resistant and 36%; steroid sensitive). Results: Mean age at diagnosis was 55 months (6 to169 months), and males outnumbered females (1.7/1). Steroid resistant patients had significantly higher platelet counts and lower PLCR, compared to steroid sensitive group. Regarding area under the ROC curve, low MPV, high PDW and low PLCR showed relatively acceptable correlation with steroid resistance. Conclusion: Increased platelet counts in addition to low PLCR are the suggestive indicators of steroid resistance in children with idiopathic nephrotic syndrome.
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Santilli, Francesca, Rossella Liani, Patrizia Di Fulvio, Gloria Formoso, Paola Simeone, Romina Tripaldi, Thor Ueland, Pål Aukrust, and Giovanni Davì. "Increased circulating resistin is associated with insulin resistance, oxidative stress and platelet activation in type 2 diabetes mellitus." Thrombosis and Haemostasis 116, no. 12 (November 2016): 1089–99. http://dx.doi.org/10.1160/th16-06-0471.
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SummaryResistin is an adipokine that promotes inflammation and insulin resistance by targeting several cells including platelets. We hypothesised that in type 2 diabetes (T2DM), resistin may foster in vivo oxidative stress, thromboxane-dependent platelet activation and platelet-derived inflammatory proteins release, key determinants of atherothrombosis. A cross-sectional comparison of circulating resistin, sCD40L, as a marker of platelet-mediated inflammation, asymmetric dimethylarginine (ADMA), endothelial dysfunction marker, Dickkopf (DKK)-1, reflecting the inflammatory interaction between platelets and endothelial cells, and urinary 8-iso-PGF2α and 11-dehydro-TxB2, reflecting in vivo lipid peroxidation and platelet activation, respectively, was performed between 79 T2DM patients and 30 healthy subjects. Furthermore, we investigated the effects of the α-glucosidase inhibitor acarbose and the PPARγ agonist rosiglitazone, targeting hyperglycaemia or insulin resistance, versus placebo, in 28 and 18 T2DM subjects, respectively. Age- and gender-adjusted serum resistin levels were significantly higher in patients than in controls. HOMA (β=0.266, p=0.017) and 11-dehydro-TXB2 (β=0.354, p=0.002) independently predicted resistin levels. A 20-week treatment with acarbose was associated with significant reductions (p=0.001) in serum resistin, DKK-1, urinary 11-dehydro-TXB2 and 8-iso-PGF2α with direct correlations between the change in serum resistin and in other variables. A 24-week rosiglitazone treatment on top of metformin was associated with significant decreases in resistin, DKK-1, 11-dehydro-TXB2 and 8-iso-PGF2α, in parallel with HOMA decrease. In conclusion, resistin, antagonising insulin action in part through PPARγ activation, may favour insulin resistance and enhance oxidative stress, endothelial dysfunction and platelet activation. The adipokine-platelet interactions may be involved in platelet insulin resistance and their consequent pro-aggregatory phenotype in this setting.
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Dellas, Claudia, Katrin Schäfer, Ilonka Rohm, Mareike Lankeit, Thomas Ellrott, Vivien Faustin, Joachim Riggert, Gerd Hasenfuss, and Stavros Konstantinides. "Absence of leptin resistance in platelets from morbidly obese individuals may contribute to the increased thrombosis risk in obesity." Thrombosis and Haemostasis 100, no. 12 (2008): 1123–29. http://dx.doi.org/10.1160/th08-05-0314.
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SummaryClinical studies have shown that elevated leptin levels are an independent cardiovascular risk factor. However, little is known about the existence of platelet resistance to leptin in the setting of obesity. We examined the effects of leptin on platelet aggregation in morbidly obese subjects (n=40; BMI, 41.6 ± 1.1 kg/m2; leptin, 49.7 ± 3.4 ng/ml) in comparison to normal-weight controls (n=36; BMI, 23.3 ± 0.4 kg/m2; leptin, 6.5 ± 0.7 ng/ml).The aggregatory response to increasing concentrations of adenosine diphosphate (ADP) (2, 3, 4, and 5 µM) was significantly increased in platelets from obese compared to lean donors, reflecting a left shift in the dose-response curve. Plasma leptin levels, but not BMI, were significantly higher in subjects with stronger (above the median) compared to weaker (below the median) platelet aggregation at all ADP concentrations tested. In further experiments, stimulation (preincubation) with leptin (500 ng/ml) promoted ADP-induced platelet aggregation by approximately 25%, and there was no difference between platelets from obese and those from lean donors regarding the responsiveness to leptin (p=0.99). Western blotting revealed that leptin induced phosphorylation of JAK2 and STAT3 to a similar extent in platelets from both groups. Expression of potential mediators of leptin resistance (SOCS3 and PTP1B) also did not differ in platelets from obese and control subjects. In conclusion, our data indicate that platelets from obese donors show increased aggregatory response to ADP, and that this might partly be the consequence of increased circulating leptin levels. Platelets from obese donors are not resistant to the enhancing effects of leptin on ADPinduced platelet aggregation.
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Sloan, Anthony, Christine Lee-Poturalski, Theresa Elder, Peggy Harris, Gino Cioffi, Alankrita Raghavan, John Willis, et al. "STEM-04. PLATELETS DRIVE GLIOBLASTOMA ONCOGENESIS BY ENHANCING THE GLIOMA STEM CELL PHENOTYPE." Neuro-Oncology 22, Supplement_2 (November 2020): ii197. http://dx.doi.org/10.1093/neuonc/noaa215.821.
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Abstract Glioblastoma (GBM) is recognized as one of the deadliest forms of cancer, despite aggressive therapy consisting of maximal surgical resection followed by concurrent radiation and chemotherapy, the median survival remains ~12 months. Glioma stem cells (GSCs) possess potent tumor-initiating properties and comprise a cellular hierarchy that is responsible for treatment resistance and progression. Specifically targeting GSCs has been considered a promising therapeutic approach, however no clear method has been identified. Histologically, it is known that GSCs are found in perivascular and pseudsopalisading regions of GBM. Similarly, platelet aggregates are often found in pseudsopalisading necrotic regions, suggesting a potential interaction between platelets and GSCs due to their spatial locations. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Our work aimed to understand the crosstalk between GSCs and platelets within GBM solid tumors that work to enhance disease progression and treatment resistance. Our clinical studies suggest elevated platelet counts positively correlate with tumor growth and negatively correlate to overall patient survival. We found platelets and GSC co-localization in GBM solid tissue; platelet exposure to GSCs results in increased proliferation of GSCs specifically, by increasing the self-renewing capacity of GSCs in a dose dependent manner, and resulted in an increased “Stem-like” transcriptional pattern. Inhibiting the GSC-platelet interaction results in a decrease in GSC renewal and stemness. These results introduce a novel interaction between GSCs and platelets and elucidate a novel therapeutic approach specifically targeting GSCs by disrupting the GSC-platelet interaction.
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Sloan, Anthony, Christine Lee-Poturalski, Theresa Elder, Peggy Harris, Amber Kerstetter-Fogle, Gino Cioffi, Alankrita Raghavan, et al. "STEM-08. PLATELETS DRIVES GLIOBLASTOMA ONCOGENESIS BY ENHANCING THE GLIOMA STEM CELL PHENOTYPE." Neuro-Oncology 22, Supplement_2 (November 2020): ii198. http://dx.doi.org/10.1093/neuonc/noaa215.825.
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Abstract Glioblastoma (GBM) is recognized as one of the deadliest forms of cancer, despite aggressive therapy consisting of maximal surgical resection followed by concurrent radiation and chemotherapy, the median survival remains ~15 months. Glioma stem cells (GSCs) possess potent tumor-initiating properties and comprise a cellular hierarchy that is responsible for treatment resistance and progression. Specifically targeting GSCs has been considered a promising therapeutic approach, however no clear method has been identified. Histologically, it is known that GSCs are found in perivascular and pseudsopalisading regions of GBM. Similarly, platelet aggregates are often found in pseudsopalisading necrotic regions, suggesting a potential interaction between platelets and GSCs due to their spatial locations. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Our work aimed to understand the crosstalk between GSCs and platelets within GBM solid tumors that work to enhance disease progression and treatment resistance. Our clinical studies suggest elevated platelet counts positively correlate with tumor growth and negatively correlate to overall patient survival. We found platelets and GSC co-localization in GBM solid tissue; platelet exposure to GSCs results in increased proliferation of GSCs specifically, by increasing the self-renewing capacity of GSCs in a dose dependent manner, and resulted in an increased “Stem-like” transcriptional pattern. Consequently, inhibiting the GSC-platelet interaction results in a decrease in GSC renewal and stemness. These results introduce a novel interaction between GSCs and platelets and elucidate a novel therapeutic approach specifically targeting GSCs by disrupting the GSC-platelet interaction.
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Cortelazzo, Sergio, Monica Galli, Donatella Castagna, Piera Viero, Giovanni de Gaetano, and Tiziano Barbui. "Increased Response to Arachidonic Acid and U-46619 and Resistance to Inhibitory Prostaglandins in Patients with Chronic Myeloproliferative Disorders." Thrombosis and Haemostasis 59, no. 01 (1988): 073–76. http://dx.doi.org/10.1055/s-0038-1642568.
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SummaryIn patients with myeloproliferative disorders (MPD) a group of related diseases of the bone marrow stem cell and recurrent haemorrhagic and/or thrombotic complications, the production of aggregating prostaglandins (PGs) may be normal or slightly reduced, while PGI2 production is normal. However, MPD platelet sensitivity to antiaggregatory PGs is still unknown.We studied the potency of PGD2, PGI2 and PGEi as inhibitors of platelet aggregation induced by threshold aggregating concentrations of arachidonic acid and U-46619-analogue of the cyclic endoperoxide PGH2 in 20 patients with MPD in comparison with healthy controls, with the aim of evaluating the sensitivity of MPD platelets to antiaggregatory PGs. In these patients platelet prostanoid metabolism was normal. However, the functional response of platelets to aggregating and antiaggregating prostanoids was shifted towards potentially increased platelet aggregation response. These findings could have a clinical relevance in view of the haemostatic and thrombotic complications so frequent in MPD.
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Berent and Sinzinger. "Aspirin - resistance? A few critical considerations on definition, terminology, diagnosis, clinical value, natural course of atherosclerotic disease, and therapeutic consequences." Vasa 40, no. 6 (November 1, 2011): 429–38. http://dx.doi.org/10.1024/0301-1526/a000145.
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Based upon various platelet function tests and the fact that patients experience vascular events despite taking acetylsalicylic acid (ASA or aspirin), it has been suggested that patients may become resistant to the action of this pharmacological compound. However, the term aspirin resistance was created almost two decades ago but is still not defined. Platelet function tests are not standardized, providing conflicting information and cut-off values are arbitrarily set. Intertest comparison reveals low agreement. Even point of care tests have been introduced before appropriate validation. Inflammation may activate platelets, co-medication(s) may interfere significantly with aspirin action on platelets. Platelet function and Cox-inhibition are only some of the effects of aspirin on haemostatic regulation. One single test is not reliable to identify an altered response. Therefore, it may be more appropriate to speak about treatment failure to aspirin therapy than using the term aspirin resistance. There is no evidence based justification from either the laboratory or the clinical point of view for platelet function testing in patients taking aspirin as well as from an economic standpoint. Until evidence based data from controlled studies will be available the term aspirin resistance should not be further used. A more robust monitoring of factors resulting in cardiovascular events such as inflammation is recommended.
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Rukoyatkina, Natalia, Valentina Shpakova, Julia Sudnitsyna, Michael Panteleev, Stephanie Makhoul, Stepan Gambaryan, and Kerstin Jurk. "Curcumin at Low Doses Potentiates and at High Doses Inhibits ABT-737-Induced Platelet Apoptosis." International Journal of Molecular Sciences 22, no. 10 (May 20, 2021): 5405. http://dx.doi.org/10.3390/ijms22105405.
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Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions.
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Takano, Katsuhiro, and Yukio Ozaki. "Monitoring of anti-platelet therapy and anti-platelet drug resistance." Nosotchu 30, no. 6 (2008): 953–59. http://dx.doi.org/10.3995/jstroke.30.953.
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Fernandez-Patron, Carlos, Maria Martinez-Cuesta, Eduardo Salas, Grzegorz Sawicki, Mieczyslaw Wozniak, Sandra Davidge, and Marek Radomski. "Differential Regulation of Platelet Aggregation by Matrix Metalloproteinases-9 and -2." Thrombosis and Haemostasis 82, no. 12 (1999): 1730–35. http://dx.doi.org/10.1055/s-0037-1614906.
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SummaryWe have recently found matrix metalloproteinase-2 (MMP-2) in human platelets and reported that the release of this enzyme during platelet activation stimulates aggregation. We have now identified matrix metalloproteinase-9 (MMP-9) in human platelets and resistance-sized (~200 μm) arteries. Resting platelets released small quantities of pro-MMP-9. Maximal release of MMP-9 was detected during partial (appr. 30% maximum) aggregation with thrombin. However, maximal release of MMP-2 was associated with maximal aggregation. MMP-9 antibodies induced aggregation of resting platelets and potentiated aggregation of platelets induced by thrombin and collagen. Moreover, MMP-9 microisolated from arteries as well as recombinant human MMP-9 (0.1-30 ng/ml) inhibited thrombin and collagen-induced aggregation. We conclude that MMP-9 is an inhibitor of aggregation and in this action opposes the effects of MMP-2. The MMP-2/MMP-9 system may play an important role in the regulation of platelet-platelet and platelet-vessel wall interactions.
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Massimi, Isabella, Lavinia Lotti, Flavia Temperilli, Massimo Mancone, Gennaro Sardella, Simone Calcagno, Ombretta Turriziani, Luigi Frati, and Fabio M. Pulcinelli. "Enhanced platelet MRP4 expression and correlation with platelet function in patients under chronic aspirin treatment." Thrombosis and Haemostasis 116, no. 12 (November 2016): 1100–1110. http://dx.doi.org/10.1160/th16-04-0316.
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SummaryPlatelet multidrug resistance protein4 (MRP4)-overexpression has a role in reducing aspirin action. Aspirin in vivo treatment enhances platelet MRP4 expression and MRP4 mediated transport inhibition reduces platelet function and delays thrombus formation. The aim of our work was to verify whether MRP4 expression is enhanced in platelets obtained from patients under chronic aspirin treatment and whether it correlates with residual platelet reactivity. We evaluated changes on mRNA and protein-MRP4 expression and platelet aggregation in four populations: healthy volunteers (HV), aspirin-free control population (CTR), patients who started the treatment less than one month ago (ASA<1 month patients) and aspirinated patients who started the treatment more than two months ago (ASA>2 months patients). In platelets obtained from ASA>2 months patients, it was found a statistically significant MRP4 enhancement of both mRNA and protein expression compared to HV, CTR and ASA<1 month patients. Platelets obtained from ASA>2 months patients that present high levels of platelet MRP4, have higher serum TxB2 levels and collagen-induced platelet aggregation compared to patient with low levels of MRP4 in platelets. In addition collagen induced platelet aggregation is higher in in vitro aspirinated platelets obtained from patients with high levels of MRP4 patients compared to those obtained from patients with low MRP4 levels. We can assert that, in patients under chronic aspirin treatment, platelets that present high MRP4 levels have an increase of residual platelet reactivity, which is due in part to incomplete COX-1 inhibition, and in part to COX-1–independent mechanism.
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White, Michael J., Simone M. Schoenwaelder, Emma C. Josefsson, Kate E. Jarman, Katya J. Henley, Chloé James, Marlyse A. Debrincat, Shaun P. Jackson, David C. S. Huang, and Benjamin T. Kile. "Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function." Blood 119, no. 18 (May 3, 2012): 4283–90. http://dx.doi.org/10.1182/blood-2011-11-394858.
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Abstract Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phosphatidylserine (PS) exposure and delaying ABT-737–induced thrombocytopenia in vivo. Despite this, steady-state platelet lifespan is normal. Casp9−/− platelets are fully capable of physiologic hemostatic responses and functional regulation of adhesive integrins in response to agonist. These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function.
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Vogt, Katja, Shailaja Mahajan-Thakur, Robert Wolf, Susanne Bröderdorf, Conny Vogel, Andreas Böhm, Christoph Ritter, et al. "Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins." Thrombosis and Haemostasis 118, no. 01 (2018): 132–42. http://dx.doi.org/10.1160/th17-04-0291.
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AbstractSphingosine-1-phosphate (S1P) is a potent lipid mediator released from activated platelets by an adenosine triphosphate (ATP)-dependent export mechanism. A candidate transport protein is the multidrug resistance protein 4 (MRP4/ABCC4), an ATP-dependent transporter highly expressed in platelets. Furthermore, several statins are known to affect platelet functions and exhibit antithrombotic properties. This study determines the involvement of MRP4 in the transport of S1P and a possible interference by statins. Transport studies in membrane vesicles of Sf9 cells containing recombinant human MRP4 revealed that MRP4 mediates ATP-dependent transport of fluorescein- and tritium-labelled S1P. Also, ATP-dependent S1P transport in platelet membrane vesicles containing endogenous MRP4 was inhibited by the MRP inhibitor MK571 and the MRP4-selective compound Ceefourin-1. Confocal microscopy using fluorescein-labelled S1P as well as boron-dipyrromethene (BODIPY)-labelled sphingosine indicated association of S1P and MRP4 in human platelets. In MRP4-deficient mice, agonist-induced S1P secretion was reduced compared with matched wild-type C57Bl/6 mice and platelet S1P concentrations were lower. Fluvastatin and rosuvastatin interfered with MRP4 function inhibiting ATP-dependent cGMP (cyclic guanosine monophosphate) uptake into MRP4-containing vesicles, inhibited MRP4-mediated S1P transport in vitro and significantly attenuated endogenous S1P release from agonist-activated platelet ex vivo. These data suggest that release of S1P from platelets depends on MRP4 and statins can interfere with this transport process. Potentially, this may be relevant for the pleiotropic anti-inflammatory effects of statins and their effect on modulating atherothrombosis.
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Pérez-Campos Mayoral, Laura, María del Socorro Pina-Canseco, Eduardo Lorenzo Pérez-Campos, María Teresa Hernández-Huerta, Edgar Zenten´-Galindo, and Ruth Martínez-Cruz. "Efecto de n-acetilglucosamina sobre plaquetas." RA RIÓ GUENDARUYUBI 1, no. 1 (September 14, 2017): 10–13. http://dx.doi.org/10.53331/rar.v1i1.0873.
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The treatment of platelets with various amino-sugars such as glucosamine, N-acetylglucosamine, N-acetyl neuraminic acid and others is capable of inducing: changes in shape, increased levels of free calcium, the exposure of phosphatidylserine on platelet surfaces, in addition to reducing the release of ATP and PF4 and inhibiting platelet aggregation. The objective of this study was to evaluate the effect of N-acetylglucosa- mine on the platelets of subjects with resistance to insulin compared with healthy subjects. The platelets (80,000 platelets/mL) of subjects with resistance to insulin were washed and then incu- bated with N-acetylglucosamine for 10 minutes and marked with the antibodies anti-PAC-1 and anti-CD62P bonded to fluorochromes and Ca2+ by means of a Fluo-3 union. Our results indicate that N-acetylglucosamine inhibits thrombin-in- duced intraplatelet calcium, the joining of antibodies anti-GPIIb/IIIa and anti-P-selectine.
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Dropinski, Jerzy, Bogdan Jakiela, Marek Sanak, Wojciech Wegrzyn, Marta Biernat, Sylwia Dziedzina, Hanna Plutecka, and Andrew Szczeklik. "The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin." Thrombosis and Haemostasis 98, no. 07 (2007): 201–9. http://dx.doi.org/10.1160/th06-12-0722.
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SummaryWe searched for additional anti-platelet effects of clopidogrel in coronary artery disease (CAD) patients treated with aspirin. Response to clopidogrel was also stratified according to aspirin resistance. Out of 76 screened aspirin-treated CAD male patients, five were aspirin-resistant based on arachidonic acid (AA) and ADP aggregometry.These five patients and 15 aspirin-sensitive patients entered the proper study. Platelet function was assessed at baseline and after one week of additional clopidogrel treatment using aggregometry, flow cytometry (ADP, TRAP-6) and platelet reactivity index (PRI) based on VASP (vasodilatorstimulated phosphoprotein) expression.We evaluated the same markers in 15 healthy men after aspirin treatment. In healthy subjects aspirin did not affect resting or ADP-induced activated GPIIb/IIIa and P-selectin expression. The P-selectin expression on ADP-activated platelets was increased (p<0.01) in aspirin treated ASA-resistant CAD patients as compared to ASA-sensitive group or aspirin-treated healthy subjects. Clopidogrel significantly decreased ADP and AA-induced platelet aggregation and overcame aspirin resistance in four of five patients. Expression of ADP-induced activation markers was significantly lowered after clopidogrel in all patients.Out of 20 patients,five did not respond to clopidogrel (<10% inhibition of ADP aggregation), and this group showed no change in expression of ADPinduced activation markers after clopidogrel. Clopidogrel treatment significantly reduced PRI only in the clopidogrel-sensitive group. In conclusion, the addition of clopidogrel to aspirin provides greater inhibition of platelets and can overcome aspirin resistance. Flow cytometric analysis of platelets is useful for monitoring of clopidogrel therapy.
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Hillman, Robert S. "Platelet Aspirin Resistance Detection and Validation." Journal of the American College of Cardiology 47, no. 12 (June 2006): 2565. http://dx.doi.org/10.1016/j.jacc.2006.03.021.
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Xiang, Yao-Zu. "Adrenoreceptors, platelet reactivity and clopidogrel resistance." Thrombosis and Haemostasis 100, no. 05 (2008): 729–30. http://dx.doi.org/10.1160/th08-09-0608.
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Lenting, Peter J., and Cécile V. Denis. "Platelet von Willebrand factor: sweet resistance." Blood 122, no. 25 (December 12, 2013): 4006–7. http://dx.doi.org/10.1182/blood-2013-10-533174.
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Howard, Patricia A. "Aspirin Resistance." Annals of Pharmacotherapy 36, no. 10 (October 2002): 1620–24. http://dx.doi.org/10.1345/aph.1c013.
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OBJECTIVE: To review the literature addressing the problem of aspirin resistance in patients with vascular disease. DATA SOURCES: A MEDLINE search (1966–February 2002) was performed. Key search terms included aspirin, resistance, resistant, failure, tolerance, and nonresponder. English-language studies were identified as well as pertinent references from these articles. DATA SYNTHESIS: Aspirin resistance has been reported in patients with cardiovascular, cerebrovascular, and peripheral vascular disease. Because of differences in the definition of resistance, variations in detection methods, and a lack of controlled trials, the true significance of the problem remains unknown. Multiple mechanisms for resistance have been proposed, including increased reactivity to platelet aggregating factors, genetic polymorphism, and alternate pathways for thromboxane synthesis. The studies to date have failed to demonstrate consistent relationships between aspirin's platelet-inhibiting effects, the impact of dosage escalation, and clinical outcomes. CONCLUSIONS: For many patients, aspirin is an effective antithrombotic agent. However, patients taking aspirin may demonstrate highly variable responses to in vitro tests for platelet aggregation and may experience breakthrough thromboembolic events. Although this phenomenon has been termed aspirin resistance, the lack of a uniform definition or agreement on diagnostic criteria precludes definitive recommendations at this time. In addition, strategies are needed to identify patients at risk for aspirin resistance who might benefit from alternative or combined antiplatelet therapy.
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Barale, Cristina, and Isabella Russo. "Influence of Cardiometabolic Risk Factors on Platelet Function." International Journal of Molecular Sciences 21, no. 2 (January 17, 2020): 623. http://dx.doi.org/10.3390/ijms21020623.
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Platelets are key players in the thrombotic processes. The alterations of platelet function due to the occurrence of metabolic disorders contribute to an increased trend to thrombus formation and arterial occlusion, thus playing a major role in the increased risk of atherothrombotic events in patients with cardiometabolic risk factors. Several lines of evidence strongly correlate metabolic disorders such as obesity, a classical condition of insulin resistance, dyslipidemia, and impaired glucose homeostasis with cardiovascular diseases. The presence of these clinical features together with hypertension and disturbed microhemorrheology are responsible for the prothrombotic tendency due, at least partially, to platelet hyperaggregability and hyperactivation. A number of clinical platelet markers are elevated in obese and type 2 diabetes (T2DM) patients, including the mean platelet volume, circulating levels of platelet microparticles, oxidation products, platelet-derived soluble P-selectin and CD40L, thus contributing to an intersection between obesity, inflammation, and thrombosis. In subjects with insulin resistance and T2DM some defects depend on a reduced sensitivity to mediators—such as nitric oxide and prostacyclin—playing a physiological role in the control of platelet aggregability. Furthermore, other alterations occur only in relation to hyperglycemia. In this review, the main cardiometabolic risk factors, all components of metabolic syndrome involved in the prothrombotic tendency, will be taken into account considering some of the mechanisms involved in the alterations of platelet function resulting in platelet hyperactivation.
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Ezzeroug Ezzraimi, Amina, Nadji Hannachi, Antoine Mariotti, Clara Rolland, Anthony Levasseur, Sophie Alexandra Baron, Jean-Marc Rolain, and Laurence Camoin-Jau. "The Antibacterial Effect of Platelets on Escherichia coli Strains." Biomedicines 10, no. 7 (June 28, 2022): 1533. http://dx.doi.org/10.3390/biomedicines10071533.
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Platelets play an important role in defense against pathogens; however, the interaction between Escherichia coli and platelets has not been well described and detailed. Our goal was to study the interaction between platelets and selected strains of E. coli in order to evaluate the antibacterial effect of platelets and to assess bacterial effects on platelet activation. Washed platelets and supernatants of pre-activated platelets were incubated with five clinical colistin-resistant and five laboratory colistin-sensitive strains of E. coli in order to study bacterial growth. Platelet activation was measured with flow cytometry by evaluating CD62P expression. To identify the difference in strain behavior toward platelets, a pangenome analysis using Roary and O-antigen serotyping was carried out. Both whole platelets and the supernatant of activated platelets inhibited growth of three laboratory colistin-sensitive strains. In contrast, platelets promoted growth of the other strains. There was a negative correlation between platelet activation and bacterial growth. The Roary results showed no logical clustering to explain the mechanism of platelet resistance. The diversity of the responses might be due to strains of different types of O-antigen. Our results show a bidirectional interaction between platelets and E. coli whose expression is dependent on the bacterial strain involved.
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Guthikonda, Sasidhar, Kirankumar Mangalpally, Rajnikant Patel, Timothy DeLao, Angela L. Bergeron, Jing-Fei Dong, Eli I. Lev, Muthiah Vaduganathan, and Neal S. Kleiman. "Increased platelet sensitivity among individuals with aspirin resistance – Platelet aggregation to submaximal concentration of arachidonic acid predicts response to antiplatelet therapy." Thrombosis and Haemostasis 100, no. 07 (2008): 83–89. http://dx.doi.org/10.1160/th07-10-0590.
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SummaryAspirin ‘resistance’ (AR) is a phenomenon of uncertain etiology describing decreased platelet inhibition by aspirin. We studied whether (i) platelets inAR demonstrate increased basal sensitivity to a lower degree of stimulation and (ii) platelet aggregation with submaximal stimulation could predict responses to aspirin. Serum thromboxane B2 (TxB2) levels and platelet aggregation with light transmission aggregometry (LTA ) were measured at baseline and 24 hours after 325 mg aspirin administration in 58 healthy subjects. AR was defined as the upper sixth of LTA (≥ 12%) to 1.5 mM AA. Baseline platelet aggregation with sub-maximal concentrations of agonists [ADP 2 µM, arachidonic acid (AA) 0.75 mM, collagen 0.375 and 0.5 µg/ml] was greater in AR subjects compared with non-AR subjects, but not with higher concentrations (ADP 5 µM and 20 µM, AA 1.5 mM and collagen 1 µg/ml). Post-aspirin platelet aggregation was elevated in AR subjects with both submaximal and maximal stimulation. Baseline and post-aspirin serumTxB2 were higher inAR subjects and decreased further with ex-vivo COX -1 inhibition, suggesting incompletely suppressed COX -1 activity. Pre-aspirin platelet aggregation to 0.75 AA demonstrated a dichotomous response with 29/58 subjects having aggregation ≤15% and 29/58 subjects having aggregation ≥75%. In the high aggregation group 28% had AR compared to 6% in the non-AR group (p=0.04). In conclusion, platelets in AR subjects demonstrate increased basal sensitivity to submaximal stimulation, which could predict responses to antiplatelet therapy.
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Wiśniewski, Adam, and Karolina Filipska. "The Phenomenon of Clopidogrel High On-Treatment Platelet Reactivity in Ischemic Stroke Subjects: A Comprehensive Review." International Journal of Molecular Sciences 21, no. 17 (September 3, 2020): 6408. http://dx.doi.org/10.3390/ijms21176408.
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Clopidogrel is increasingly being used for the secondary prevention of ischemic stroke according to the updated guidelines on acute stroke management. Failure to achieve a drug response is referred to as clopidogrel resistance. Similarly, a higher activation of platelets during clopidogrel therapy—high on-treatment platelet reactivity—is equivalent to a reduced effectiveness of a therapy. Clopidogrel resistance is considered to be a common and multifactorial phenomenon that significantly limits the efficacy of antiplatelet agents. The aim of the current study is to review the latest literature data to identify the prevalance and predictors of clopidogrel high on-treatment platelet reactivity among stroke subjects and to establish the potential impact on clinical outcomes and prognosis. Clinical databases were searched by two independent researchers to select relevant papers on the topic, including all types of articles. Several important predictors contributing to clopidogrel resistance were identified, including genetic polymorphisms, the concomitant use of other drugs, or vascular risk factors, in particular nonsmoking and diabetes. Clopidogrel high on-treatment platelet reactivity has a negative impact on the clinical course of stroke, worsens the early- and long-term prognoses, and increases the risk of recurrent vascular events. Platelet function testing should be considered in selected stroke individuals, especially those predisposed to clopidogrel resistance, for whom an improvement in the efficacy of antiplatelet therapy is essential. This particular group may become the greatest beneficiaries of the modification of existing therapy based on platelet function monitoring.
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Weyrich, A. S., G. A. Solis, K. S. Li, T. N. Tulenko, and W. P. Santamore. "Platelet amplification of vasospasm." American Journal of Physiology-Heart and Circulatory Physiology 263, no. 2 (August 1, 1992): H349—H358. http://dx.doi.org/10.1152/ajpheart.1992.263.2.h349.
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Platelets may accentuate vasoconstriction in stenotic arteries capable of vasomotion. We examined the interaction of platelets, stenosis, and arterial vasoconstriction in normal and stenotic arteries with intact endothelium. Beagle carotid arteries (n = 38) were isolated, removed, and placed in an in vitro perfusion system. Platelet-rich plasma (PRP) or platelet-poor plasma (PPP) were perfused through the arteries under constant pressure (100 mmHg) and a fixed distal resistance. In intact arteries without a stenosis, angiotensin II (ANG II) decreased luminal diameter without altering flow during PRP perfusion. After creating an intraluminal stenosis, vasoconstriction produced by ANG II resulted in near total cessation of flow. During PRP perfusion, this effect was amplified, demonstrating suppression of flow at significantly (P less than 0.05) lower concentrations of ANG II (PRP, ED50 = 0.03 +/- 0.01 x 10(-8) M) compared with arteries perfused with PPP (PPP, ED50 = 2.7 +/- 0.8 x 10(-8) M). This accentuated vasoconstrictor response in the presence of platelets was not blocked by SKF 96148 (a thromboxane A2 antagonist) but was abolished by ketanserin (a 5-HT2-serotonergic blocker). This increased sensitivity to vasoconstriction was not due to significant platelet plugging inasmuch as no cyclic flow reductions were observed, aspirin (acetylsalicylic acid) did not prevent this accentuated vasoconstrictor response, and adventitial administration of nitroglycerin restored flow to baseline levels. These studies illustrate that 1) platelets amplify the effect of vasoconstrictors in stenotic arteries, 2) this amplification of vasoconstriction is primarily due to platelet release of serotonin, and 3) the amplification occurs in the absence of significant platelet plugging and endothelial damage.
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Sagar, Rebecca C., Ramzi A. Ajjan, and Khalid M. Naseem. "Non-Traditional Pathways for Platelet Pathophysiology in Diabetes: Implications for Future Therapeutic Targets." International Journal of Molecular Sciences 23, no. 9 (April 29, 2022): 4973. http://dx.doi.org/10.3390/ijms23094973.
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Cardiovascular complications remain the leading cause of morbidity and mortality in individuals with diabetes, driven by interlinked metabolic, inflammatory, and thrombotic changes. Hyperglycaemia, insulin resistance/deficiency, dyslipidaemia, and associated oxidative stress have been linked to abnormal platelet function leading to hyperactivity, and thus increasing vascular thrombotic risk. However, emerging evidence suggests platelets also contribute to low-grade inflammation and additionally possess the ability to interact with circulating immune cells, further driving vascular thrombo-inflammatory pathways. This narrative review highlights the role of platelets in inflammatory and immune processes beyond typical thrombotic effects and the impact these mechanisms have on cardiovascular disease in diabetes. We discuss pathways for platelet-induced inflammation and how platelet reprogramming in diabetes contributes to the high cardiovascular risk that characterises this population. Fully understanding the mechanistic pathways for platelet-induced vascular pathology will allow for the development of more effective management strategies that deal with the causes rather than the consequences of platelet function abnormalities in diabetes.
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Holada, Karel, Adela Brouckova, Jan Simak, William A. Gahl, and Jaroslav G. Vostal. "Platelet Cellular Prion Protein (PRPC) Is Associated with alpha Granules." Blood 104, no. 11 (November 16, 2004): 3882. http://dx.doi.org/10.1182/blood.v104.11.3882.3882.
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Abstract The cellular prion protein (PrPc) is a membrane glycoprotein expressed on many human cells including blood platelets. We have previously shown that human platelets rapidly up-regulate PrPc on their plasma membranes after activation (Holada et al., Br J Haematol.1998;103(1):276–82.). Our preliminary results also showed that platelet PrPc is resistant to cleavage by phosphatidylinositol specific phospholipase C (PIPLC). In this study we investigated intracellular localization of platelet PrPc and its resistance to PIPLC of different origin and under different experimental conditions. To determine the intracellular localization of platelet PrPc, we used flow cytometry and PrPc directed monoclonal antibodies (MAb) 1562 and 6H4, which recognize residues 109–112, and 144–152, in human PrPc sequence, respectively. The specificity of MAb binding was confirmed by its inhibition with competing peptides. We compared the increase in PrPc expression after platelet activation with increase in expression of P-selectin (CD62) - an α-granular protein, and LIMP (CD63) - a lysosomal and δ-granular protein. Gel filtered platelets were activated by ADP (1–100 μM) or TRAP (0.5–50 μM). Increasing concentrations of agonists induced coexpression of P-selectin and PrPc on the platelet surface at lower concentrations than were required for expression of LIMP (e.g. 5 μM ADP vs. 50 μM ADP to reach 40% of maximal expression), suggesting that PrPc did not associate with lysosomes. To further address the question of the origin of intraplatelet PrPc, we evaluated the expression of platelet PrPc in two patients with Hermansky-Pudlak (H/P) syndrome and two patients with Grey platelet syndrome (GPS). H/P platelets have a low number of δ-granules, but normal numbers of α-granules and lysosomes. When compared to controls, the H/P platelets had decreased mepacrine staining, demonstrating a defect of δ-granules. The expression of LIMP was equivalent on resting control (15.2 geometric mean of FL1 (GMF)) and H/P platelets (14.4 GMF), but was substantially decreased on H/P platelets after full platelet activation (38.2 vs. 168.8 GMF). In comparison, similar levels of PrPc and α-granular P-selectin were expressed on normal (35.7 and 726 GMF) and H/P patient (33.9 and 689 GMF) activated platelets. Platelets of GPS patients are deficient in α-granules. Resting GPS platelets demonstrated higher expression of P-selectin (9.9 GMF) and PrPc (25.8 GMF) than normal platelets (4.9 and 14.3 GMF, respectively). In contrast to normal platelets, GPS platelets failed to up-regulate P-selectin (76 vs. 653 GMF) and PrPc (30.1 vs. 59.9 GMF) after activation. In order to confirm a resistance of PrPc to PIPLC in normal platelets, the presence of glycosyl-phosphatidylinositol (GPI) anchor was verified by the treatment of platelet PrPc with hydrofluoric acid, which resulted in a 2–4 kDa decrease of its molecular weight corresponding to the removal of GPI anchor. Interestingly, PIPLC enzymes of three different origins (B. thuringiensis, B. cereus, B. subtilis) did not cleave GPI anchor even after the solubilization of platelet membranes by Triton X-100, which should make anchor more accessible to the enzyme. In conclusion, our results suggest that platelet intracellular PrPc is associated with α-granules, but not with lysosomes, and δ-granules. Platelet membrane PrPc is resistant to PIPLC, likely due to GPI-modification rather than GPI accessibility.
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Jedlitschky, Gabriele, Andreas Greinacher, and Heyo K. Kroemer. "Transporters in human platelets: physiologic function and impact for pharmacotherapy." Blood 119, no. 15 (April 12, 2012): 3394–402. http://dx.doi.org/10.1182/blood-2011-09-336933.
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Platelets store signaling molecules (eg, serotonin and ADP) within their granules. Transporters mediate accumulation of these molecules in platelet granules and, on platelet activation, their translocation across the plasma membrane. The balance between transporter-mediated uptake and elimination of signaling molecules and drugs in platelets determines their intracellular concentrations and effects. Several members of the 2 major transporter families, ATP-binding cassette (ABC) transporters and solute carriers (SLCs), have been identified in platelets. An example of an ABC transporter is MRP4 (ABCC4), which facilitates ADP accumulation in dense granules. MRP4 is a versatile transporter, and various additional functions have been proposed, notably lipid mediator release and a role in aspirin resistance. Several other ABC proteins have been detected in platelets with functions in glutathione and lipid homeostasis. The serotonin transporter (SERT, SLC6A4) in the platelet plasma membrane represents a well-characterized example of the SLC family. Moreover, recent experiments indicate expression of OATP2B1 (SLCO2B1), a high affinity transporter for certain statins, in platelets. Changes in transporter localization and expression can affect platelet function and drug sensitivity. This review summarizes available data on the physiologic and pharmacologic role of transporters in platelets.
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Goncharov, M. D., A. A. Savchenko, Yu I. Grinshtein, I. I. Gvozdev, A. A. Kosinova, and T. S. Mongush. "Aspirin Resistance as a Result of Impaired Interaction of Platelets and Neutrophils in Patients with Coronary Heart Disease." Rational Pharmacotherapy in Cardiology 17, no. 1 (March 3, 2021): 16–22. http://dx.doi.org/10.20996/1819-6446-2021-01-07.
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Aim. To study the relationship between the levels of synthesis of reactive oxygen species (ROS) by platelets and neutrophils in patients with coronary heart disease (CHD) before and after coronary artery bypass grafting (CABG), depending on sensitivity to acetylsalicylic acid (ASA).Material and methods. The study included 95 patients with coronary artery disease who are indicated for CABG surgery. The control group consisted of 30 healthy donors. The antiplatelet therapy was stopped for at least 5 days before CABG. In the postoperative period, from the first day, all patients were received 100 mg of an enteric form of acetylsalicylic acid (ASA). Resistance to ASA was determined at the level of platelet aggregation with arachidonic acid ≥20% by optical agregometry at least at one observation point: before CABG, on 1-3 day and on 8-10 day after surgery. We evaluated the spontaneous and induced lucigenin-dependent chemiluminescence (CL) of platelets (ADP induction) and neutrophils (zymosan induction) by the exit time to maximum intensity (Tmax), maximum intensity (Imax) and area (S) under the CL curve.Results. 70.5% sensitive (sASA) and 29.5% resistant (rASA) to ASA patients were revealed. Prior to CABG, in sASA patients, the Imax of spontaneous and zymosan-induced neutrophil CL and CL platelet activity was increased relative to control values. Tmax of spontaneous platelet CL, Imax and S under the ADP-induced platelet CL curve were lower in sASA patients, if to compare with rASA patients. On the 1st and 8-10th day after CABG in sASA patients, the CL indicators of neutrophil and platelet activity also remained elevated compared to control values. On the 1st day after CABG decreased levels of S under the spontaneous CL curve of neutrophils in rASA patients was established compared with sASA patients, and increased levels of Imax and S under the curve of induced neutrophil CL were detected in comparison with the control range. In rASA patients, the values of Tmax of spontaneous platelet CL decreased in relation to the values detected in the control group and sASA patients. On the 8–10th day after CABG, most indicators of spontaneous and zymosan-induced CL neutrophils in rASA patients were also increased compared to control values. In rASA patients a positive correlation of Imax-induced CL was found (r=0.83) on the 1st day after CABG and negative correlations of Tmax of spontaneous CL (r=- 0.75) and S under the curve induced CL (r=-0.70) on the 8-10th day were detected between platelets and neutrophils.Conclusion. In sASA patients with coronary heart disease before and after CABG, a high level of synthesis of superoxide radical by neutrophils and platelets was detected. The relationship between the levels of the synthesis of superoxide radical by neutrophils and platelets was found only after CABG in rASA patients. Increased synthesis of superoxide radical due to metabolic and regulatory relationships in neutrophils and platelets stimulates pro-inflammatory processes in coronary artery disease and determines the sensitivity of platelets to ASA.
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Neki, NS. "Clopidogrel Resistance: Current Issues." Journal of Enam Medical College 6, no. 1 (February 9, 2016): 38–46. http://dx.doi.org/10.3329/jemc.v6i1.26381.
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Antiplatelet agents are mainly used in the prevention and management of atherothrombotic complications. Dual antiplatelet therapy, combining aspirin and clopidogrel, is the standard care for patients having acute coronary syndromes or undergoing percutaneous coronary intervention according to the current ACC/AHA and ESC guidelines. But in spite of administration of dual antiplatelet therapy, some patients develop recurrent cardiovascular ischemic events especially stent thrombosis which is a serious clinical problem. Antiplatelet response to clopidogrel varies widely among patients based on ex vivo platelet function measurements. Clopidogrel is an effective inhibitor of platelet activation and aggregation due to its selective and irreversible blockade of the P2Y12 receptor. Patients who display little attenuation of platelet reactivity with clopidogrel therapy are labeled as low or nonresponders or clopidogrel resistant. The mechanism of clopidogrel resistance remains incompletely defined but there are certain clinical, cellular and genetic factors including polymorphisms responsible for therapeutic failure. Currently there is no standardized or widely accepted definition of clopidogrel resistance. The future may soon be realised in the routine measurement of platelet activity in the same way that blood pressure, cholesterol and blood sugar are followed to help guide the therapy, thus improving the care for millions of people. This review focuses on the methods used to identify patients with clopidogrel resistance, the underlying mechanisms, metabolism, clinical significance and current therapeutic strategies to overcome clopidogrel resistance.J Enam Med Col 2016; 6(1): 38-46
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Schaphorst, Kane L., Eddie Chiang, Keri N. Jacobs, Ari Zaiman, Viswanathan Natarajan, Frederick Wigley, and Joe G. N. Garcia. "Role of sphingosine-1 phosphate in the enhancement of endothelial barrier integrity by platelet-released products." American Journal of Physiology-Lung Cellular and Molecular Physiology 285, no. 1 (July 2003): L258—L267. http://dx.doi.org/10.1152/ajplung.00311.2002.
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In vitro and in vivo evidence indicates that circulating platelets affect both vascular integrity and hemostasis. How platelets enhance the permeability barrier of the vascular endothelium is not well understood. We measured the effect of isolated human platelets on human pulmonary artery endothelial cell (EC) barrier integrity by monitoring transmonolayer electrical resistance. EC barrier function was significantly increased by the addition of platelets (∼40% maximum, 2.5 × 106platelets/ml). Platelet supernatants, derived from 2.5 × 106platelets/ml, reproduced the barrier enhancement and reversed the barrier dysfunction produced by the edemagenic agonist thrombin, which implicates a soluble barrier-promoting factor. The barrier-enhancing effect of platelet supernatants was heat stable but was attenuated by either charcoal delipidation (suggesting a vasoactive lipid mediator) or pertussis toxin, implying involvement of a Giα-coupled receptor signal transduction pathway. Sphingosine-1-phosphate (S1P), a sphingolipid that is released from activated platelets, is known to ligate G protein-coupled EC differentiation gene (EDG) receptors, increase EC electrical resistance, and reorganize the actin cytoskeleton (Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, Bamberg JR, and English D. J Clin Invest 108: 689–701, 2001). Infection of EC with an adenoviral vector expressing an antisense oligonucleotide directed against EDG-1 but not infection with control vector attenuated the barrier-enhancing effect of both platelet supernatants and S1P. These results indicate that a major physiologically relevant vascular barrier-protective mediator produced by human platelets is S1P.