Academic literature on the topic 'Platelet resistance'
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Journal articles on the topic "Platelet resistance"
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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.
Dissertations / Theses on the topic "Platelet resistance"
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Blair, Thomas Anthony. "Investigations into the role of phosphoinositide 3-kinase (P13K) in platelet priming and antiplatelet resistance." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.691257.
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Platelets play a pivotal role in haemostasis and at sites of vascular injury arrest bleeding. Unregulated haemostasis leads to thrombosis and coronary artery disease (CAD). The 'gold-standard' preventative measure to combat CAD is administration of antiplatelet compounds that target TxA2/ ADP amplification pathways. Some CAD patients are 'resistant' to anti platelet therapy and these patients often have hyperactive platelets. In combination with physiological stimuli, primers potentiate platelet functional responses. Primers are known to function via a Pl3K-dependent mechanism and may induce antiplatelet resistance. The aims of this PhD project were: (i) establish the role of primers in anti platelet resistance and (ii) characterise the PI3K isoform involved in primer-mediated platelet potentiation. First, I studied the role of primers in anti platelet resistance by treating platelets with ARC66096 (P2Y12 inhibitor) and/or aspirin in the presence/absence of primers (IGF-l, TPO and adrenaline). This study demonstrated that primers could drive antiplatelet resistance. Furthermore Pl3K-mediated mechanisms were responsible for IGF-l/TPO-mediated resistance, while Pl3K-dependent and independent mechanisms were responsible for adrenaline-mediated resistance.
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Modica, Angelo. "Inflammation, platelet aggregation and prognosis in acute myocardial infarction." Doctoral thesis, Umeå : Umeå university, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-32519.
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Cheng, Xi. "Prevalence, profile, predictors, and natural history of aspirin resistance measured by the ultegra rapid platelet function assay-asa in patients with coronary artery disease." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B33708708.
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Lam, Lap-fung, and 林立峰. "Flow cytometric analysis of intra-platelet VASP for evaluation of clopidogrel resistance in ischemic heart disease patients undergoingpercutaneous coronary intervention." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48421200.
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Ischemic heart disease (IHD) is the most common cause of death around the world. The underlying cause of IHD is myocardial ischemia as a result of progressive narrowing of coronary arteries due to atherosclerosis with potential thrombotic complications mediated by platelets. In addition to the role in hemostasis, platelets are increasingly recognized as an important mediator in this atherothrombotic disease. Basic management of IHD lies on medical therapy and coronary revascularization procedures. Percutaneous coronary intervention (PCI) is a commonly used revascularization procedure in the treatment of IHD especially for relief and reduction of symptoms. On the other hand, antiplatelet therapy is often administrated to patients undergoing PCI in an attempt to prevent major adverse cardiac events (MACE) following the procedures. However not all patients respond to the same degree of the antiplatelet therapy and some still develop MACE or stent thrombosis in the presence of the treatment with antiplatelet drugs.
Recently a flow cytometric-based assay has been developed to monitor the effect of the antiplatelet drug, particularly the P2Y12 receptor antagonist, in patients treated with this kind of drug. This assay measures the activity of platelets as platelet reactivity index (PRI) based on the phosphorylation state of an intracellular platelet protein called vasodilator stimulated phosphoprotein (VASP). The measured value of PRI is inversely related to the response of patient to the antiplatelet drug.
In this study, the response of patients to the P2Y12 receptor antagonist Clopidogrel was investigated following PCI. The PRI of patients was found to be significantly lower than normal subjects without taking this drug, indicating the therapeutic effect of this drug on the patients. However nearly one-third of patients (17 out of 59) studied were found to be non-responsive to clopidogrel treatment based on a cut-off established in this study for classifying patients into responders or non-responders. Furthermore, significant difference between the two types of stents used in PCI procedure, namely bare metal stent (BMS) and drug eluting stent (DES), was observed in the study. Patients receiving DES had nearly three times higher percentage of being non-responsive to clopidogrel than the BMS counterpart (45% vs. 16%, p<0.028). This study provides evidence that DES may be implicated in the non-responsiveness or drug resistance of clopidogrel in patient undergoing PCI.published_or_final_version
Pathology
Master
Master of Medical Sciences
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Alabdullatif, Meshari. "Understanding the Resistance and Virulence Mechanisms of Staphylococcus Epidermidis Triggered During Skin Disinfection, Blood Production and Storage." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38661.
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Bacterial contamination of platelet concentrates (PCs) represents the highest post-transfusion infectious risk. The skin flora bacterium Staphylococcus epidermidis has been reported to be the predominant aerobic contaminant of PCs. The Ramirez' group has shown that S. epidermidis can form surface-attached bacterial aggregates known as biofilms, and can outcompete other coagulase-negative staphylococci, such as Staphylococcus capitis, in PCs. The ability of S. epidermidis to form biofilms has been linked to increased pathogenicity and missed detection during PC screening with an automated culture system (BacT/ALERT). This thesis aimed at investigating the proliferative advantage and resistance mechanisms displayed by S. epidermidis in the PC milieu. Furthermore, in an effort to enhance PC safety for transfusion patients, I studied the anti-biofilm properties of essential oils and antimicrobial peptides (AMPs). My studies aimed at improving PC safety by focussing on both the point of introduction of bacterial contaminants (blood collection), and the stage at which bacterial contaminants can form biofilms and proliferate (PC storage). S. epidermidis can be found in the skin of blood donors as biofilms, which are resistant to the blood donor skin disinfectant currently used by Canadian Blood Services, chlorhexidine-gluconate and isopropyl alcohol (CHG-IPA). Here, several plant-extracted essential oils were evaluated for their ability to enhance the anti-biofilm activity of CHG-IPA. Data revealed that the Lavandula multifida oil and its main component (linalool) greatly enhanced the activity of CHG-IPA against S. epidermidis biofilms. Furthermore, the ability of a combination of three synthetic AMPs to inhibit S. epidermidis biofilm formation during PC storage was assessed These results showed that the combination of AMPs could inhibit biofilm formation but was ineffective against pre-formed S. epidermidis biofilms. The accumulation associated protein (Aap) encoded by the aap gene, found in most S. epidermidis strains and absent in S. capitis, plays a role in biofilm formation. When S. epidermidis aap is transformed into S. capitis, this bacterium displayed increased biofilm formation and proliferated to higher concentrations compared to untransformed S. capitis and to a S. epidermidis aap deletion mutant. Based on these results, aap appears to play a role in providing S. epidermidis a proliferative advantage in PCs by enhancing biofilm formation. Lastly, the GraRS system and SepA were studied for their role in S. epidermidis resistance to platelet-derived AMPs using the synthetic AMP PD4 as a model molecule.
Results indicate that the GraS mechanism is involved in resistance towards PD4. The work presented in my thesis provides further insights into why S. epidermidis has a proliferative advantage in the PC storage environment and allows for the proposal of alternative methods to enhance PC safety for transfusion patients.
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Cheng, Xi, and 程曦. "Prevalence, profile, predictors, and natural history of aspirin resistance measured by the ultegra rapid platelet function assay-asain patients with coronary artery disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B33708708.
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Freeman, Philip. "The influence of nitric oxide and nitrite on coronary vascular resistance, platelet function and inflammation in patients undergoing revascularisation after NSTEMI and stable angina." Thesis, Cardiff University, 2018. http://orca.cf.ac.uk/114152/.
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Coronary blood flow (CBF) is principally controlled by changes in coronary vascular resistance (CVR). Low CVR helps to maintain myocardial perfusion in the presence of epicardial stenosis, therefore factors that impair the reduction of CVR will have a direct effect on CBF leading to either a narrower “effective” perfusion pressure range or reduced ability to compensate for increased demand on myocardial contraction. There are several mechanisms which may be important in the control CVR in humans including both endothelial dependent production of NO and reduction of the simple anion inorganic nitrite (a metabolite of NO) back to NO (via several putative mechanisms). The synthesis of NO by both nitric oxide synthase (NOS) and the reduction of nitrite in the coronary circulation has been the subject of many animal and human clinical studies. Reduced systemic endothelial dependent production of NO has an association with worse cardiovascular outcomes in humans, the number of potential mechanisms are large and perhaps central is the effect on CVR. The reduction of nitrite to NO is seen, in some ways, to be the perfect compensatory mechanism, particularly when endothelial function is impaired. It is easy to hypothesise that this stoichiometric balance of NO production might be responsible for the perfect regulation of CVR and thus CBF. Methods This thesis investigates the influence and effect of both endothelial production of NO and the reduction of nitrite to NO on CVR in man. First, an observational study assessing the impact of these mechanisms in patients undergoing percutaneous coronary intervention (PCI), in the treatment of both non-ST-elevation myocardial infarction and stable angina. Specifically, the metabolites of NO were measured from aortic root to coronary sinus together with the associated CVR both before and after PCI. Second, using a systemic infusion of sodium nitrite (NaNO2) in NSTEMI patients to assess the effect of nitrite reduction on CVR during PCI. The systemic nitrite concentration was increased 8-fold in the same experimental conditions as the observational study. Third, beyond CVR control the influence of NO and nitrite was also assessed in terms of platelet reactivity and systemic inflammatory cytokines in the NSTEMI cohort both with and without NaNO2 infusion. Results NSTEMI patients have a net increase in NO metabolites across the coronary circulation unlike healthy controls (historical data) and stable angina patients. This net increase is lost following PCI and is associated with a significant rise in CVR. Stable angina patients appear to compensate with increase collateral circulation and not NO synthesis. An 8-fold increase in nitrite concentration has no effect on CVR or platelet reactivity in NSTEMI patients. Conclusions In NSTEMI patients a net aorta to coronary sinus NO synthesis appears to be important to maintain a low CVR and thus CBF when haemodynamically significant epicardial disease is present. After the epicardial disease is treated this net increase in NOx (Nitric Oxide metabolites), is lost and is associated with an acute increase in CVR. Stable angina patients have no net increase in NOx across the coronary circulation and after revascularisation have no change in CVR, this may reflect an alternate mechanism of compensation and microvascular perfusion maintained by collateral circulation as evident by the increase CFI. Despite the perfect environment for the reduction of nitrite to NO we saw no influence of an 8-fold increase in serum nitrite concentration on CVR in patients with NSTEMI either before or after PCI, suggesting that nitrite reduction to NO plays no role in CBF regulation in NSTEMI patients. Nitrite reduction depends on conditions that are found predominantly in the capillary bed or venules, thus any mechanism would need to rely on a feedback mechanism to signal back to the arterioles (where much of resistance change is created). Despite hypotheses by others that this may occur by the close arrangement of venules to arterioles, this appears not to be the case in NSTEMI patients. Other clinically relevant and important mechanisms also appear to be unaffected by this increase in serum nitrite, residual platelet function and cytokine concentrations at 24 hours.
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Jacomassi, Mayara D\'Auria. "Envolvimento da ativação de PAFR frente à quimioterapia no fenômeno de repopulação de melanomas." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-28022019-083226/.
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Um dos desafios recorrentes na prática clínica da Oncologia é o processo de repopulação, no qual células tumorais resistentes à terapia são capazes de proliferar e reconstituir o tumor. No entanto, os mecanismos envolvidos neste fenômeno ainda foram pouco explorados, sendo necessário melhor compreendê-los para evitar a falha terapêutica. Melanomas são bons modelos para estudar repopulação devido às baixas taxas de sobrevida livre de progressão e às altas taxas de resistência às terapias associadas a este tipo de tumor sólido. Sabe-se que a exposição de células tumorais a condições estressoras do microambiente, como hipóxia e hipóxia/reoxigenação, bem como ao próprio tratamento antitumoral, são pressões seletivas frequentemente encontradas em tumores sólidos que favorecem a resistência às terapias e a repopulação tumoral. Estudos prévios indicam que a sinalização mediada pelo Fator de Ativação de Plaquetas (PAF), um lipídio bioativo relacionado à diversas funções fisiológicas, e de seu receptor, PAFR, está associada com a resistência de células de melanoma aos tratamentos citotóxicos e com crescimento tumoral. Portanto, este trabalho teve como objetivo investigar o envolvimento da sinalização de PAFR frente às condições estressoras descritas acima no fenômeno de repopulação de melanomas. Os resultados de espectrometria de massa indicaram que hipóxia aumentou a geração de PAF nas linhagens de melanoma humano SKmel05 e A375, mas não na A375M, embora este aumento não tenha sido observado após a reoxigenação. Além disso, mostraram que SKmel37 exibiu os maiores níveis basais de PAF, aumentando substancialmente sua geração em diferentes tempos de exposição à hipóxia e hipóxia/reoxigenação. Investigamos também a geração de outros ligantes de PAFR, porém nenhum deles foi encontrado nas amostras. Os resultados de detecção de PAFR por Western Blot e/ou citometria de fluxo revelaram que os níveis proteicos não foram modulados por estas condições em nenhuma das linhagens e que, em termos basais, SKmel37 e SKmel05 apresentaram os maiores níveis. Estas linhagens foram, portanto, submetidas a ensaios de proliferação, os quais evidenciaram que frente ao tratamento com o antagonista de PAFR, WEB2086, em condições de hipóxia e hipóxia/reoxigenação, apenas as células SKmel37 tiveram sua proliferação reduzida e morfologia associada à morte. Ensaios de incorporação de iodeto de propídio indicaram que o tratamento destas células expostas à hipóxia/reoxigenação com WEB2086 levou a acúmulo em SG2M, morte celular e sensibilização à cisplatina. Além disso, imunofluorescência de cortes congelados de tumores induzidos com SKmel37 revelou que houve acúmulo de PAFR em áreas hipóxicas e em seu entorno. Em relação ao modelo de exposição à tratamentos antitumorais, por sua vez, curvas de concentração e tempo com Vemurafenib mostraram que SKmel37 e A375 foram resistentes à droga, ao passo que SKmel05 e UACC62 foram sensíveis. Além disso, WEB2086 potencializou o efeito de morte induzido por Vemurafenib nas linhagens sensíveis, mas não afetou as resistentes. Considerando os aspectos clínicos de resposta inicial com posterior desencadeamento de repopulação, seguimos com as linhagens sensíveis e verificamos por citometria que esta droga aumentou ROS em ambas as linhagens, mas só aumentou PAFR extracelular na SKmel05. O tratamento combinado potencializou a geração de ROS e levou a ativação de caspase3/7 apenas na SKmel05. Esta linhagem foi então submetida a ensaios clonogênicos cujos resultados mostraram que o tratamento com Vemurafenib reduziu o número de clones e que WEB2086 não potencializou este efeito. Assim, o conjunto de resultados apresentados evidencia que a sinalização de PAFR participa dos desfechos de sobrevivência frente à hipóxia/reoxigenação e/ou tratamentos antitumorais, podendo, de alguma forma, contribuir com a repopulação de melanomasOne of the recurrent challenges in the clinical practice of Oncology is the process of repopulation, in which therapy-resistant tumor cells can proliferate and reconstitute the tumor. However, the mechanisms involved in this phenomenon were still little explored. The understanding of these events is, therefore, needed to avoid therapeutic failure. Melanomas are good models for studying repopulation due to the low rates of progression-free survival and the high rates of resistance to therapies associated to this type of solid tumor. It is known that the exposure of tumor cells to microenvironmental stress conditions, such as hypoxia and hypoxia/reoxygenation, as well as the exposure to antitumor treatment itself, are selective pressures frequently found in solid tumors that favor therapy resistance and tumor repopulation. Previous studies have indicated that the signaling mediated by the Platelet Activation Factor (PAF), a bioactive lipid related to various physiological functions, and its receptor, PAFR, is associated with resistance of melanoma cells to cytotoxic treatments and with tumor growth. Therefore, the aim of this study was to investigate the involvement of PAFR signaling upon the adverse conditions described above in the phenomenon of melanoma repopulation. Mass spectrometry results indicated that hypoxia increased the generation of PAF in human melanoma cell lines SKmel05 and A375, but not in A375M, although this increase was not observed after reoxygenation. In addition, they showed that SKmel37 exhibited the highest PAF basal levels, whose generation increased substantially after different times of hypoxia and hypoxia/reoxygenation exposure. We also investigated the generation of other PAFR ligands, but none were found in the samples. The results of PAFR detection by Western Blot and/or flow cytometry revealed that protein levels were not modulated by these conditions in any of the cell lines and that, at baseline, SKmel37 and SKmel05 showed the highest levels. These lines were therefore submitted to proliferation assays, which showed that the treatment with the PAFR antagonist, WEB2086, under conditions of hypoxia and hypoxia/reoxygenation, led to proliferation reduction and death-associated morphology in SKmel37 cells only. Propidium iodide incorporation studies indicated that the treatment of these cells exposed to hypoxia/reoxygenation with WEB2086 led to accumulation in SG2M, cell death and cisplatin sensitization. In addition, immunofluorescence of frozen sections of SKmel37-induced tumors revealed that PAFR was found accumulated in hypoxic areas and its surroundings. Regarding the model of exposure to antitumor treatments, concentration and time curves with Vemurafenib showed that SKmel37 and A375 were resistant to the drug, whereas SKmel05 and UACC62 were sensitive. In addition, WEB2086 potentiated the effect of Vemurafenib-induced death on sensitive cell lines but did not affect the resistant ones. Considering the clinical aspects of initial response with subsequent repopulation triggering, we continued using the sensitive cell lines and we verified by cytometry that this drug increased ROS in both cell lines but only increased extracellular PAFR in SKmel05. The combined treatment potentiated the generation of ROS and led to the activation of caspase3/7 in SKmel05 only. This cell line was then submitted to clonogenic assays whose results showed that treatment with Vemurafenib reduced the number of clones and that WEB2086 did not potentiate this effect. Thus, the set of results presented highlights that PAFR signaling participates in the survival outcomes upon hypoxia/reoxygenation and/or antitumor treatments, and may, in some way, contribute to the repopulation of mel
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Pereira, Angélica Costa Aranha Camacho 1976. "Efeito de um bloqueador do receptor PDGF na adipogênese de camundongos tratados com dieta hiperlipídica." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311204.
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Orientador: Mario Jose Abdalla SaadDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A obesidade é hoje considerada um problema de saúde pública. Essa condição é caracterizada pelo aumento do peso corporal, mais especificamente do tecido adiposo branco. A adipogênese (diferenciação do pré-adipócito em adipócito) é um fenômeno complexo e não muito bem caracterizado. Recentes estudos mostraram que os préadipócitos estão localizadas nas paredes dos vasos que irrigam o tecido adiposo. Estas células estão presentes exclusivamente neste tecido e expressam alguns marcadores, dentre eles o PDGFRß. O PDGFRß é um receptor tirosina quinase cujo papel na migração, proliferação e diferenciação de diversos tipos celulares tem sido extensivamente estudado. O AG1296 (6,7- dimetoxi-2-fenil-quinoxalina) é um potente inibidor do receptor PDGF, pertencente à classe da quinoxalinas. Deste modo, levando-se em consideração o papel do receptor PDGF no crescimento e proliferação celulares e o fato de que as células PDGFR_ positivas provenientes do tecido adiposo possuem alto potencial adipogênico, neste estudo investigamos o efeito do AG1296 na adipogênese de camundongos submetidos à dieta hiperlipídica e à dieta padrão. Nós também investigamos se essa inibição afetaria a sensibilidade à insulina desses grupos estudados. Para tanto, camundongos Swiss machos com seis semanas de vida foram divididos em quatro grupos: o grupo Controle que recebeu dieta padrão, o grupo C+AG1296 que recebeu dieta padrão e tratamento com AG1296, o grupo DH que recebeu dieta hiperlipídica somente e o grupo DH+AG1296 que recebeu dieta hiperlipídica e tratamento com AG1296. Peso corpóreo e ingestão alimentar foram medidos diariamente durante o tratamento (7 ou 15 dias). Através de Western blot, foram quantificadas as principais proteínas pró-adipogênicas (SREBP-1c, C/EBP? e PPAR?) e a fosforilação das principais proteínas da via da insulina (IR, IRS1 e AKT). Nossos resultados indicaram que nos animais controle, após 15 dias de tratamento com AG1296, houve uma redução nas três frações de tecido adiposo, associada a uma redução em algumas das proteínas adipogênicas, além de uma melhora na sinalização insulínica em fígado e músculo e uma redução na glicemia de jejum. Além disso, nos animais submetidos à dieta hiperlipídica, após 7 dias de tratamento com AG1296, foi possível observar uma redução nas proteínas adipogênicas e uma redução na fração epididimal do tecido adiposo. Houve também uma melhora na sinalização insulínica e na tolerância à glicose. Com isso, podemos sugerir que a inibição do PDGFRß pode ter um papel importante na adipogênese e na sinalização insulínica e pode ser um alvo potencial para prevenção da obesidade e resistência à insulina
Abstract: Obesity can be defined as a disease in which body fat is excessively accumulated. Adipogenesis is a complex and not completely known phenomenon. Recent studies showed that adipocyte progenitor cells are exclusively found in adipose tissue and express some markers like PDGFRß (Platelet-derived growth factor ß). AG1296 (6,7-dimethoxy-2-phenyl-quinoxaline) is a potent and selective inhibitor of PDGF receptor kinase. In this context, the main objective of this work was to investigate if the inhibition of PDGF receptor through AG1296 would be able to affect white adipose tissue generation in high-fat-diet-fed and standard-chow-fed mice. We also investigated if this inhibition would have an effect on the insulin sensitivity in these studied groups. For this purpose, six-week-old male Swiss mice were divided into four groups and assigned to receive the following diet and/or treatment: the control group (C) received standard rodent diet, the second group (C + AG1296) received standard rodent diet plus AG1296 (50 mg/Kg/day by gavage), the third group (HFD) received high fat diet (55% calories from fat, 29% calories from carbohydrate and 16% from protein) and the fourth group (HFD+AG1296) received high fat diet plus AG1296. Body weight and food intake were measured during the treatment (7 and 15 days). After that, tissues (epididymal, retroperitoneal and mesenteric adipose tissue, liver and muscle) were extracted and processed. Through Western blot analysis, we were able to quantify the main proteins related to adipogenesis (SREBP-1c, C/EBP? e PPAR?) and the phosphorylation of the main proteins from insulin pathway (IR, IRS1 and Akt). Our results indicated that on control mice, after 15 days of treatment with AG1296, there was a reduction on adipose fat pad, associated with reduction in some adipogenic proteins, an increase in insulin signaling in liver and muscle and a reduction in fasting plasma glucose. Futhermore, on mice fed a high fat diet, after 7 days of treatment with AG1296, it was possible to observe a reduction on adipogenesis proteins and a reduction in epididymal fat pad. Also, there was an improvement in insulin signaling pathway and in glucose tolerance. In conclusion, our results suggest that PDGFRß inhibition might have an important role in adipogenesis and in insulin signaling and could be a potential target for preventing obesity and insulin resistance
Mestrado
Biologia Estrutural, Celular, Molecular e do Desenvolvimento
Mestre em Ciências
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Andrade, Marianna Deway. "Alta atividade plaquetária residual em resposta ao ácido acetilsalicílico em pacientes com síndrome isquêmica miocárdica instável sem supradesnível de ST: comparação entre as fases aguda e tardia." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5131/tde-07022014-151723/.
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INTRODUÇÃO: Racional: A alta atividade plaquetária residual (AAPR) em uso do AAS é considerada um fator de mau prognóstico em portadores de síndrome isquêmica miocárdica instável (SIMI). Adicionalmente, as taxas de prevalência de AAPR verificadas em diferentes estudos realizados na fase aguda das SIMI são consideradas elevadas em relação às verificadas em portadores de doença arterial coronariana estável. Todavia, não está bem demostrado se essa elevada prevalência de AAPR diagnosticada na fase aguda das SIMI representa um fenômeno transitório, desaparecendo na fase tardia, ou se é um estado permanente, independente da fase aguda. MÉTODOS: O objetivo primário do presente estudo foi o de comparar, em pacientes com SIMI sem supradesnível do segmento ST, a resposta antiplaquetária ao AAS nas fases aguda e tardia na mesma população. Foram incluídos 70 pacientes com SIMI sem supradesnível de ST (77% com angina instável e 22% com IAM sem supra de ST), com idade média de 64,97 anos, sendo 54% do sexo feminino, todos em uso de AAS na dose de 100 a 200mg por pelo menos sete dias anteriores à inclusão. Os pacientes foram submetidos a cinco testes de agregação plaquetária na fase aguda, e os mesmos testes foram repetidos na fase tardia, três meses depois: VerifyNowAspirin®, agregometria de sangue total (AST) com ácido aracdônico (AA) e colágeno, tromboxane B2 sérico, PFA-100. RESULTADOS: De acordo com os testes COX-1 específicos (VFN e AST com AA), a AAPR em uso do AAS foi mais prevalente na fase aguda das SIMI do que na fase tardia (VFN: 32,1% versus 16%, p=0,049; e AST com AA: 31,4% versus 12,8%, p=0,015). Os testes não específicos (AST com colágeno, PFA) e o teste bioquímico não conseguiram demonstrar diferenças entre as fases. A correlação entre os cinco testes realizados foi considerada fraca ou moderada. CONCLUSÃO: A alta prevalência de AAPR, apesar do uso da AAS durante as SIMI, reflete mais provavelmente um estado de hiper-reatividade plaquetária transitória, que se reverte na fase crônica e estável da DAC, de acordo com os testes COX-1 específicos. A correlação entre os testes plaquetários foi apenas moderada nos dois cenáriosBACKGROUND: The high residual platelet activity (HRPA) in response to acetylsalicilic acid (ASA) is considered a poor prognostic factor in patients with acute coronary syndromes (ACS). Additionally, the HRPA prevalence rates reported by different studies in ACS patients are considered high compared to those reported in patients with stable coronary artery disease. However, it is not well demonstrated whether this high HRPA prevalence diagnosed during the acute phase represents a transient phenomenon, disappearing in the late phase, or if it is a permanent state, independent of the acute phase. The aim of this study was to compare platelet aggregation in response to ASA during the ACS acute phase with the platelet aggregation in chronic stable phase. METHODS: Inclusion of patients with non ST ACS who were on aspirin at a dose of 100mg to 200mg per day for at least seven days prior to inclusion. We conducted five tests of platelet aggregation in the first 48 hours and repeated them three months later: VerifyNow Aspirin® (VFN), Whole Blood aggregometry (WBA) with arachidonic acid (AA) and collagen, thromboxane B2, PFA-100®. We analyzed 70 patients (77% with unstable angina and 22% with non ST AMI), mean age 64.97 years, 54% female. According to the COX-1 specific tests, the HRPA was more frequent in the acute phase than in the chronic phase (VerifyNowAspirin®: 31.4% versus 12.8%, p=0.015; and WBA with AA: 32.1% versus 16%, p=0.049; respectively). The non specific tests (AST with collagen and PFA) and the biochemical test sTXB2 failed to show differences between the phases. The correlation between the five tests was considered weak or moderate. CONCLUSION: The high prevalence of RPA despite the use of aspirin during the acute phase of the SCA most likely reflects a state of transient platelet hyperreactivity, which is reversed in the chronic phase. The correlation between platelet tests was only moderate in both scenarios
Books on the topic "Platelet resistance"
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Zheng, Zhido. Measurement of fracture resistance of silicon carbide platelet reinforced alumina. Ottawa: National Library of Canada, 1993.
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Wijdicks, Eelco F. M., and Sarah L. Clark. Antiplatelet Agents. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190684747.003.0009.
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Antiplatelet agents are commonly used in vascular medicine and cardiology, but also in the pharmacologic management of patients with ischemic stroke. Aspirin alone remains the mainstay of therapy for secondary stroke prevention. Several landmark studies for the optimal duration and dose of antiplatelet therapy in stroke prevention are discussed. Dual antiplatelet therapy is needed after carotid artery stenting. Situations where antiplatelet agents also come into play are endovascular procedures associated with procedure-related thrombi. Antiplatelet agents have different mechanisms of action, and each will be discussed. Testing of platelet function and the issue of antiplatelet resistance and discontinuation of antiplatelet agents before procedures will be discussed in this Chapter.
Book chapters on the topic "Platelet resistance"
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Hughes, A. D. "The Effect of Platelet-Derived Growth Factor on Tone and [Ca2+]i in Vascular Smooth Muscle." In The Resistance Arteries, 225–33. Totowa, NJ: Humana Press, 1994. http://dx.doi.org/10.1007/978-1-4757-2296-3_21.
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Pisano, Antonio. "Electric Current, Resistance, Circuits, Thermoelectric Effect: Platelet Aggregometry, Pressure Transducers, and Temperature Monitoring." In Physics for Anesthesiologists and Intensivists, 125–40. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-72047-6_11.
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Manrique, R. V., and V. Manrique. "Resistance of Platelets to Prostacyclin." In Prostacyclin and Its Stable Analogue Iloprost, 57–63. Berlin, Heidelberg: Springer Berlin Heidelberg, 1987. http://dx.doi.org/10.1007/978-3-642-71499-3_7.
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van den Brand, Marcel J. B. M., and Maarten L. Simoons. "The Use of Abciximab in Therapy Resistant Unstable Angina." In Platelet Glycoprotein IIb/IIIa Inhibitors in Cardiovascular Disease, 143–68. Totowa, NJ: Humana Press, 1999. http://dx.doi.org/10.1007/978-1-59259-724-6_8.
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van den Brand, Marcel J. B. M., and Maarten L. Simoons. "The Use of Abciximab in Therapy-Resistant Unstable Angina." In Platelet Glycoprotein IIb/IIIa Inhibitors in Cardiovascular Disease, 203–31. Totowa, NJ: Humana Press, 2003. http://dx.doi.org/10.1007/978-1-59259-376-7_9.
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Ogweno, Gordon, and Edwin Murungi. "Controversies in Platelet Functions in Diabetes Mellitus Type 1." In Type 1 Diabetes Mellitus [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.108276.
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Individuals with diabetes mellitus (DM) are at high risk of thrombosis in which hyperactive platelets are implicated. The platelet hyperactivity has been linked to hyperglycemia. This hypothesis is supported by studies in type II diabetes mellitus showing increased sensitivity of platelets to stimulating agonists in the context of tissue resistance to high-circulating insulin. However, controversy still exists regarding the altered platelet functions in type 1 diabetes mellitus (T1DM) and the link to modifying factors such as blood glucose, hyperlipidemia, metabolic acidosis and insulin treatment. Moreover, increased insulin dosage or treatment appears to have antagonistic actions: diminished functions at low doses and enhanced activation at high doses, the switch being attributable to insulin-like growth factor. The physiological role of insulin in suppressing platelet activation is lost in T1DM, a scenario that favors increased platelet sensitivity to stimulating agonists. Furthermore, the response to antiplatelet agents and statins is sub-optimal in diabetics presenting clinical and research knowledge gap regarding the ideal antiplatelet treatment in DM in general and T1DM in particular. This chapter reviews the unique characteristics of platelet functions in T1DM highlighting the controversial areas linking unique behavior of platelets and the abnormal response to therapeutic interventions.
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Amoryna, D. M., Z. Mukthar, and H. Hariman. "Acetyl salicylic acid resistance and inhibition to platelet aggregation." In Stem Cell Oncology, 333–36. CRC Press, 2018. http://dx.doi.org/10.1201/9781351190152-71.
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Becker, Richard C., and Frederick A. Spencer. "Combination Pharmacotherapy." In Fibrinolytic and Antithrombotic Therapy. Oxford University Press, 2006. http://dx.doi.org/10.1093/oso/9780195155648.003.0017.
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The goal of improving coronary arterial patency, microcirculatory blood flow, and myocardial perfusion represents the essence of fibrinolytic–adjunctive therapy combinations. Because fibrinolytic resistance, patency without perfusion, and reocclusion are platelet-mediated phenomena, considerable emphasis has been placed on the development of platelet antagonists. Coronary arterial thrombi consist of platelets and fibrin bound in a tightly packed meshwork. Platelets modify the intrinsic properties of the fibrin network, causing changes in permeability and vasoelasticity, which decrease fibrinolysis rates. The addition of aspirin and the glycoprotein (GP) IIb/IIIa receptor antagonist abciximab modulates the interaction of platelets and fibrin, improving both accessibility to fibrinolytics and the overall rates of fibrinolysis (Collet et al., 2001). The Thrombolysis in Myocardial Infarction (TIMI) 14 trial (Antman et al., 1999) randomized 888 patients with ST-segment elevation myocardial infarction (MI) to receive (1) accelerated tissue plasminogen activator (tPA; ≤100 mg) plus standard dose of unfractionated heparin (UFH); (2) tPA (920 mg bolus) plus abciximab (0.25 mg/kg bolus, 7 μg/min); (3) streptokinase (800,000 to 1.5 million units) and low-dose UFH; or (4) abciximab plus low-dose UFH. TIMI 3 flow rates 90 minutes from treatment initiation were 52%, 53%, 42%, and 32%, respectively. In subsequent dose/strategy studies, a combination of tPA (35 mg) plus abciximab and tPA (15 mg bolus, 31 mg over 60 minutes) plus abciximab revealed 63% and 73% TIMI 3 flow rates, respectively. Rates of major hemorrhage were similar in all tPA treatment groups. The Strategies for Patency Enhancement in the Emergency Department (SPEED) trial (SPEED Group, 2000) included two phases. Phase A (n = 241) randomized patients to receive either abciximab (bolus plus infusion) alone or combined with 5 U, 7.5 U, 10 U, 5 U + 2.5 U, or 5U + 5 U of reteplase. Phase B tested the best strategy from phase A (abciximab plus 5 U + 5 U of reteplase) against 10 U + 10 U of reteplase. In phase A, 62% of the abciximab–reteplase 5 U + 5 U patient group had TIMI 3 flow rates at 60 to 90 minutes vs. 27% of those given abciximab alone (p = .001).
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Csönge, Lajos, Ágnes Bozsik, Zoltán T. Bagi, Róbert Gyuris, Dóra K. Csönge, and János Kónya. "Thermal Manipulation of Human Bone Collagen Membrane (SoftBone) and Platelet-Rich Fibrin (PRF) Membranes." In Collagen Biomaterial [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.102817.
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Resorbable barrier membranes, including platelet-rich fibrin (PRF) and collagen membranes, can play a key role in guided bone regeneration surgeries (GBR) in dentistry. A new collagen membrane made of partially decalcified allogeneic cortical bone, termed SoftBone membrane (SB), was produced by West Hungarian Regional Tissue Bank. It can be easily adapted to diverse surfaces. Fresh and freeze-dried folded-PRF membranes were compared with freeze-dried SB. Important properties of membranes were reported (moisture content, rehydration capacity, and resistance against proteolytic enzyme). The SB exhibited the best resistance against enzymatic digestion on day 21, its weight was 34% of the original. Fresh F-PRF (folded PRF) disintegrated on the 11th day, while the freeze-dried F-PRF membrane dissolved completely on day 8. The thermal manipulation of the F-PRF membrane using freeze-drying has advantages and also disadvantages in comparison to the fresh one.
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Santonocito, Cristina, Filippo Sanfilippo, and Marc O. Maybauer. "Bivalirudin for Alternative Anticoagulation in Heparin-Induced Thrombocytopenia During ECMO." In Extracorporeal Membrane Oxygenation, edited by Marc O. Maybauer, 153–60. Oxford University Press, 2022. http://dx.doi.org/10.1093/med/9780197521304.003.0014.
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Systemic anticoagulation with unfractionated heparin (UFH) is most commonly used for systemic anticoagulation during extracorporeal membrane oxygenation (ECMO). However, some cases need alternative strategies of anticoagulation because the occurrence of heparin-induced thrombocytopenia (HIT) or heparin resistance (HR). The most commonly used alternative is represented by the direct thrombin inhibitor (DTI) bivalirudin, which has been increasingly used not only for ECMO anticoagulation but also during cardiopulmonary bypass (CPB) and percutaneous coronary intervention (PCI). Another option is the combined use of UFH with an antiplatelet medication that reduces platelet aggregation and risk of thrombosis in patients with HIT. This chapter describes a clinical scenario in which after 1 week of ECMO support and treatment with UFH a gradually developing thrombocytopenia was regarded causative for HIT since other causes of thrombocytopenia were not identifiable. Laboratory assays were inconclusive, and UFH was switched to bivalirudin. After prolonged ECMO support with partial recovery, a left ventricular assist device was implanted and anticoagulation with bivalirudin continued. The case discussion is followed by a critical review of the literature and multiple-choice questions, summarizing this chapter as a concise learning and study tool for the management of patients with HIT or HR during ECMO.
Conference papers on the topic "Platelet resistance"
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Hardeman, M. R., and J. Vreeken. "TRANSIENT AGGREGATION RESISTANCE OF HUMAN PLATELET-RICH PLASMA; A NEGLECTED IN VITRO PHENOMENON WITH PHYSIOLOGICAL IMPACT." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643405.
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Due to instability in the first in vitro period, platelet-aggregometry is usually deliberately postponed until ca. 1 hour after venepuncture (VP) . At that time aggregability is fairly constant for 1 hour or more. Investigation of the period immediately followed VP, hcwever, revealed a high aggregation resistance - measured as the threshold ADP-concentration which the platelets just could resist before they aggregate maximally and irreversibly - which subsequently decreased exponentially with time. This “Transient Aggregation Resistance” (TAR) appeared to be superimposed on a stable, so called Baseline Aggregation Resistance (BAR) .The latter, measurable 60 min or more after VP, yields the “classical” threshold ADP-concentration.Parallel aggregation-studies started 6 min after VP, subsequent studies were performed every 4 min. pH was controlled during storage of PRP at rocmtenperature. Extrapolation of the TAR-curve to t=0 (i.e. time of VP) yields the maximal value:TARmax Coefficients of variation for TARmax-method: 9.4% (n=6) ; intraindividial 15% (n=15, over 3 yrs); interindividual: 51% (n=16,wide range).This TAR-phencmenon which is proven to be caused by a plasma-factor, can be influenced by dietary n-3 fattty acids and can be also inhibited by ASA,suggesting a prostanoid nature. The physiological significance of TAIfoax can be illustrated by the following findings:1. Patients with myocardial infarction, hyperlipoproteinemia, sickle cell anemia (i.e. diseases with a high risk for thrombotic complications) have low TARmax-values. 2.Individuals with “spontaneous platelet aggregation” in vitro,but asymptomatic, have positive TARmax-values. 3.There is a clear,reciproke age-dependency of TARmax It is concluded that a technique is available measuring the effect of circulating,labile platelet-aggregation influencing plasma factor(s). Furthermore, using this technique,it was found that normal fresh plasma contains a labile aggregation-inhibiting factor which is several orders of magnitude more potent than other stabile factors either present in plasma or associated with platelets. This factor is probably of prostanoid nature and might have significance as a reflection of the antithrcmbotic potential of the endothelium.
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Cortelazzo, S., D. Castagna, M. Galli, T. Barbui, and G. de Gaetano. "INCREASED RESPONSE TO ARACHIDONIC ACID AND U-46619 AND RESISTANCE TO INHIBITORY PR0STAGLANDING IN PATIENTS WITH CHRONIC MYELOPROLIFE RATIVE DISORDERS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643381.
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The potency of prostaglandins (PGs) D2, I2 and as inhibitors of platelet aggregation induced by threshold aggregating concentration (TAC) of arachidonic acid (AA) and U-46619 was determined in platelet rich plasma from 20 normal subjects and 20 patients with thrombocytosis (≥500×l09 platelets/L) secondary to myeloproliferative disorders. Patients had a significantly increased response to both AA and U-46619 (p< 0.02) than the control group (i.e. TAC for AA, mean+SD, was 0.41±0.10 mM vs 0.48±0.12 mM ; TAC for U-46619 was 220±155 nM vs 375±102 nM). In contrast, platelet sensitivity to all three inhibitoty PGs was significantly lower in patients than in normal subjects. Indeed the threshold inhibiting concentrations (nM) of PGs against AA were the following: PGD2 20.33±4.16 vs 7.00±2.62 (p< 0.001), PGI2 0.76±0.46 vs 0.34±0.22 (p< 0.01) and PGE1 11.83±3.97 vs 6.50±2.22 (p<0.001). The corresponding inhibitory concentrations (nM) against U-46619 were the following: PGD2 4.67±4.24 vs 0.76±0.30 (p< 0.02), PGI2 1.15±0.96 vs 0.03±0.01 (p< 0.0001) and PGE1 21.12±15.27 vs 0.68± 0.30 (p< 0.0001). Selective pharmacologic inhibition of TxA2 sinthase by 40 μM dazoxiben resulted in 6 out of 11 “responders” in patients and 7 out of 10 in normal subjects, a difference not statistically significant. Serum TxB2 was slightly, but not significantly lower in patients than in controls (360±143 ng vs 390±155 ng/3×109 platelets/mL). It is suggested that in patients with myeloproliferative disorders platelet arachidonate metabolism is normal, but the functional response to aggregating and antiag-gregating prostanoids is altered towards a potential hyperaggrega bility. The relevanbe of this “in vitro” finding to thrombotic or haemorragic complications in these patients remains to be establi shed.
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Lande, K., I. O. S. S. E. Kieldsen, A. Westheim, I. Aakesson, I. Hlermann, I. Eide, and K. GiesdaL. "PATIENTS WITH MILD ESSENTIAL HYPERTENSION HAVE INCREASED PLATELET SIZE AND RELEASE REACTION ANO SHOW INCREASED RECEPTOR RESPONSE TO INFUSED ADRENALINE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644261.
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Hypertensive (n = 35) and normotensive {n = 44) men all 42 years old were studied. The hypertensive (HT) had larger venous platelets than the normotensive (HT) (7.46 ± 0.10 vs 7.12 ± 0.09 10-15 1, p = 0.01). Plasma concentration of |3-thromboglobulin (BTG) was increased in arterial blood in hypertensive (40 ± 8 vs 21 ± 2 ug/1, p=0.02) while the venous values were similar in the two groups. Despite similar sampling procedure, the normotensive subjects had markedly higher BTGconcentration in venous compared to arterial blood (p≺0.01) at variance from thehypertensive where the arteriovenous difference in plasma BTG concentration was not present. Adrenaline was infused to 13 hypertensive and 12 normotensive subjects with dose gradually increasing to 0.04 pg/kg/min. Forearm blood flow was measured by strain gauge technique and relative forearm resistance calculated as mean blood pressure divided by flow. Twelve normotensive subjects (control group) received saline infusion.Change in forearm resistance reflectsβ2- activation of smooth vascular cells, change in platelet count reflects splenic liberation of platelets in response to adrenergic stimulation while change in BTG may reflect platelet release upon stimulation of α2 -receptors. Thus, middle aged men with essential hypertension show increased sensitivity to adrenaline infusion in vascular smooth muscle, spleen and platelets.
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Backhouse, C. M., D. AJ Galvin, R. A. Harper, A. C. Meek, and C. N. McCollum. "PARTICULATE CONTAMINATION OF DRUGS: THEIR EFFECT ON PLATELET KINETICS AND THE PULMONARY CIRCULATION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644867.
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More than 107 particulate contaminants >2um and many more <2um are infused daily in parenteral medications to intensive care patients. They may form emboli with aggregated platelets and damage pulmonary vasculature [1], perhaps contributing to alveolar fibrosis in very premature babies. We studied this possibility in neonatal pigs.Nineteen newborn pigs were randomised to either daily 0.2um filtered salineas controls, or infusions of particles similar to drug contaminants at 10x greater than the patient equivalent dose/kg given via subcutaneous injection portals with tunnelled central venous catheters. Four weeks later, autologous platelets were labelled with llllndium and arterial and Swann Ganz catheters inserted under general anaesthesia. Before particle or filtered saline infusion and at 5 and 20 minutes later platelet count, lung platelet uptake, mean arterial pressure (BP), pulmonary vascular resistance, pulmonary shunt and alveolar-arterial P02 difference were measured.Initially, there were no significant differences between the groups indicating no measureable effect from chronic particle dosing over 4 weeks. Within 30 sec of bolus particle injection BP fell from a mean ( ± sem) of 68.9+2.1mmHg to 61.0±2.1 (p<0.01, paired t-test) but returned to normal within 5 minutes. This was not seen with controls or particle injections given over 5 minutes. Platelet counts fell in the particle group from 660±43 (x109/L) to 584±46 at 20 minutes (p<0.01) but lung platelet accumulation was insignificant.Transient fall in blood pressure due to contaminating particles can be avoided by slow injection or 0.2um in-line filters. Particles stimulate a loss of circulating platelets but with insignificant pulmonary accumulation and no impairment of pulmonary function after 4 weeks of daily particle injection at considerably higher doses than patients receive.1. Chia C, Cattell V. The role of platelets in mesangial localisation: carbon uptake in thrombocytopaenic rats. BrJ Exp Path 1985; 66: 465-474.
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Poskitt, K. R., J. T. C. Irwin, C. M. Backhouse, and C. N. McCollum. "MICROEMBOLISATION DURING SURGICAL SHOCK: EFFECT OF PROSTAGLANDIN E1." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643450.
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Embolisation of microaggregates following major surgery may be a cause of pulmonary arterio-venous shunt and postoperative respiratory failure (1). Prostaglandin E1 may prevent intravascular aggregation and we studied this possibility in a pig model of surgical shock.Following autologous platelet labelling with Indium, 16 pigs (20-30kg) were randomised to receive a perioperative infusion of PGE1 (100ng/kg/min) or placebo. Arterial and Swann Ganz catheters were inserted under anaesthesia prior to surgery consisting of midline laparotomy, exteriorisation of small bowel 1.5 hours of aortic clamping and 1 hour of hypotension. On induction, during shock and at 3 days in survivors platelet and leucocyte count, blood radioactivity, venous aggregates (SFP), lung platelet uptake (LPU), pulmonary vascular resistance (PVR) and alveolar-arterial p02 difference (A-ad02) were measured.All results mean ± sem *p <0.05 Mann Whitney U-testDuring surgical shock, the formation of venous aggregates, the fall in circulating radiolabelled platelets and their accumulation in lungs were reduced by PGE1 (p< 0.05). BP, CVP and PWP were all lower on PGE1 and at 3 days the improvement in A-ad02 in PGE1 pigs failed to reach significance.PGE1 reduced platelet aggregate formation and their subsequent pulmonary microembolisation despite worsening shock due to vasodilation.1. McCollum CN, Campbell IT. The value of measuring intravascular platelet aggregation in the prediction of postoperative pulmonary dysfunction. Br J Surg 1979: 66; 703-707
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Gawne, D. T., Z. Qiu, T. Zhang, Y. Bao, and K. Zhang. "Abrasive Wear Resistance of Plasma-Sprayed Glass-Composite Coatings." In ITSC 2000, edited by Christopher C. Berndt. ASM International, 2000. http://dx.doi.org/10.31399/asm.cp.itsc2000p0977.
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Abstract A ball-milled mixture of glass and alumina powders has been plasma sprayed to produce alumina-glass composite coatings. The coatings have the unique advantage of a melted ceramic secondary phase parallel to the surface in an aligned platelet composite structure. The alumina raises the hardness from 300HV for pure glass coatings to 900HV for a 60wt% alumina-glass composite coating. The scratch resistance increases by a factor of three and the wear resistance by a factor of five. The glass wears by the formation and intersection of cracks. The alumina wears by fine abrasion and supports most of the sliding load. The wear resistance reached a plateau at 40-50vol% alumina, which corresponds to the changeover from a glass to a ceramic matrix. Keywords: glass composite coatings, wear, thermal spraying
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VREEKEN, J., and M. R. HARDEMAN. "FISH AND PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643404.
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The effect of two different amounts of a fish oil, corresponding to 0.75 g (2.5 mmol) and 1.5 g (5 mmol) of eicosapentaenoic acid respectively, added in a cross-over design to the normal diet of 16 healthy male volunteers, was studied. Of the various parameters investigated, the most important appeared to be a new test: “Transient Aggregation Resistance” (TAR) of platelets, a phenomenon which, due to its short half life, is hardly measured when platelet aggregation is studied according to the classic method (see M.R.Hardeman, TAR determination, this congress). Under the influence of fish oil, the half life of TAR was found significantly prolonged. This prolongation, however, was not related to the amount of fish oil used. A highly significant decrease of triglycerides was found, the effect being most pronounced in subjects with triglycerides starting values >1.0 uM. This decrease was related to the amount of fish oil used. These.results may cast light on controversies found in literature concerning the effect of fish oil on platelet aggregation . They can also help to clarify controversies about the effect of fish consumption on cardiac mortality.
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Kadushkin, Aliaksei, Anatoli Tahanovich, Anastasiya Arabey, Liudmila Shishlo, Andrey Savchanka, and Liudmila Movchan. "Assessment of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio as biomarkers of steroid resistance in patients with COPD." In Abstracts from the 17th ERS Lung Science Conference: ‘Mechanisms of Acute Exacerbation of Respiratory Disease’. European Respiratory Society, 2019. http://dx.doi.org/10.1183/23120541.lungscienceconference-2019.pp216.
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Backhouse, C. M., A. C. Meek, K. R. Poskitt, and C. N. McCollum. "PULMONARY MICROEMBOLISATION IN SURGICAL SHOCK: THE EFFECT OF CYCLO-OXYGENASE INHIBITION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643458.
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Thromboxane release from platelet microemboli during major arterial surgery may mediate depression of cardio-pulmonary function. The effect of cyclo-oxygenase inhibition by aspirin has been studied in a porcine model of aortic surgery.Following autologous platelet labelling with 111-lndium, 24 pigs (20-25kg) were randomised to low dose (LD) aspirin (0.5mg/kg), high dose (HD) aspirin (10mg/kg) or placebo.Arterial and Swann Ganz catheters were inserted prior to surgery consisting of midline laparotomy, small bowel extériorisation, 1.5 hours of aortic clamping and 1 hour shock before resuscitation. On induction, during shock and at 3 days, platelet and leucocyte counts, lung platelet uptake (LPU), venous aggregates by screen filtration (SFP), mean arterial pressure (BP), cardiac output (CO), pulmonary shunt (PS) and alveolar-arterial pO2 difference (A-adO2) were measured.During shock following aortic declamping aspirin preserved blood pressure by increasing vascular resistance rather than CO. Venous aggregates by SFP tended to be lower on aspirin with significantly reduced LPU, subsequent pulmonary shunting and A-adO2. The improvement in PS but not A-adO2 remained significant at 3 days (p<0.05).Cyclo-oxygenase inhibition improved pulmonary function during surgical shock either by inhibiting platelet microemboli or by a direct effect on pulmonary arteriovenous shunts.
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Silva, Gustavo Figueiredo da, Bruno Mattei Lopes, Vinicius Moser, and Leslie Ecker Ferreira. "Impact of pharmacogenetics on aspirin resistance: a systematic review." In XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.663.
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Background: Pharmacogenetics promises better control of diseases, such as Cardiovascular disease (CVD). Acetylsalicylic acid, aspirin, prevents the formation of an activating agent of platelet aggregation and vasoconstriction, and it is used to prevent CVD. Nevertheless, patients may have treatment failure, causing recurrence and increased mortality, due to medication adherence, drug- drug interactions, aspirin-independent thromboxane A2 synthesis or genetic variants. In this sense, genetic variants have been related with aspirin resistance (AR). Objective: To evaluate the evidence of impact of genetic variants on AR through systematic literature review. Design and setting: Systematic review. Methods: Articles published since 2009 in MEDLINE/PubMed, Cochrane, Scopus, LILACS and SCIELO were systematically screened. Results: The genetic variants rs1126643 (ITGA2), rs3842787 (PTGS1), rs20417 (PTGS2) and rs5918 (ITGB3) were the most studied. As for the relevance of the genetic variants studied, of the 64 evaluated, 14 had statistical significance (p <0.05, 95% CI) in at least one article. Among them, the following have had unanimous. Results: rs1371097 (P2RY1), rs1045642 (MDR1), rs1051931 and rs7756935 (PLA2G7), rs2071746 (HO1), rs1131882 and rs4523 (TBXA2R), rs434473 (ALOX12), rs9315042 (ALOX5AP) and rs662 (PON1). While these differ in real interference in AR: rs5918 (ITGB3), rs2243093 (GP1BA), rs1330344 (PTGS1) and rs20417 (PTGS2). Conclusion: As limitations of our study, we highlight the non-uniform methodologies of the analyzed articles, as well as population differences. It is also noteworthy that pharmacogenetics is an expanding area. Therefore, further studies are needed to better understand the association between genetic variants and AR, as well as the practical application.