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PON1 Q192R is associated with high platelet reactivity with clopidogrel in patients undergoing elective neurointervention: A prospective single-center cohort study.
Tanaka, K, Matsumoto, S, Ainiding, G, Nakahara, I, Nishi, H, Hashimoto, T, Ohta, T, Sadamasa, N, Ishibashi, R, Gomi, M, et al
PloS one. 2021;(8):e0254067
Abstract
BACKGROUND AND PURPOSE The impact of the paraoxonase-1 (PON1) polymorphism, Q192R, on platelet inhibition in response to clopidogrel remains controversial. We aimed to investigate the association between carrier status of PON1 Q192R and high platelet reactivity (HPR) with clopidogrel in patients undergoing elective neurointervention. METHODS Post-clopidogrel platelet reactivity was measured using a VerifyNow® P2Y12 assay in P2Y12 reaction units (PRU) for consecutive patients before the treatment. Genotype testing was performed for PON1 Q192R and CYP2C19*2 and *3 (no function alleles), and *17. PRU was corrected on the basis of hematocrit. We investigated associations between factors including carrying ≥1 PON1 192R allele and HPR defined as original and corrected PRU ≥208. RESULTS Of 475 patients (232 men, median age, 68 years), HPR by original and corrected PRU was observed in 259 and 199 patients (54.5% and 41.9%), respectively. Carriers of ≥1 PON1 192R allele more frequently had HPR by original and corrected PRU compared with non-carriers (91.5% vs 85.2%, P = 0.031 and 92.5% vs 85.9%, P = 0.026, respectively). In multivariate analyses, carrying ≥1 PON1 192R allele was associated with HPR by original (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.03-3.76) and corrected PRU (OR 2.34, 95% CI 1.21-4.74) after adjustment for age, sex, treatment with antihypertensive medications, hematocrit, platelet count, total cholesterol, and carrying ≥1 CYP2C19 no function allele. CONCLUSIONS Carrying ≥1 PON1 192R allele is associated with HPR by original and corrected PRU with clopidogrel in patients undergoing elective neurointervention, although alternative results related to other genetic polymorphisms cannot be excluded.
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Effect of Regular Aerobic Activity in Young Healthy Athletes on Profile of Endothelial Function and Platelet Activity.
Podgórska, K, Derkacz, A, Szahidewicz-Krupska, E, Jasiczek, J, Dobrowolski, P, Radziwon-Balicka, A, Skomro, R, Szuba, A, Mazur, G, Doroszko, A
BioMed research international. 2017;:8715909
Abstract
The aim of the study was to assess the impact of regular professional sports activity on the endothelial and platelet function in young men. The studied group were 79 young men (18-40 y, 25 athletes and 54 without any regular physical activity). The nitric oxide (NO) metabolic pathway intermediates, oxidative stress markers, mediators of inflammation, and platelet aggregation were measured. Flow mediated dilation (FMD) was studied before and after intravenous 16,0 g L-arginine infusion, which was repeated after oral administration of acetylsalicylic acid (ASA-75 mg/day) for 4 days. Both groups had similar demographic characteristics. In the athletes, there was significantly higher hsCRP level, better serum lipid profile, and lower pulse pressure. Greater baseline FMD in athletes and in response to L-arginine disappeared following ASA treatment. There were no differences in the levels of the NO pathway metabolites. The control group was characterized by higher PAI-1 following ASA treatment and sICAM-1 both at baseline and after ASA, but no differences in MDA and 6-keto-PGF-1 alpha and platelet aggregation were noted. Regular professional physical activity modulates endothelial but not platelet function and may thus exert an effect on overall cardiovascular risk.
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Randomised, double-blind, placebo-controlled study investigating the effects of inorganic nitrate on vascular function, platelet reactivity and restenosis in stable angina: protocol of the NITRATE-OCT study.
Rathod, KS, Jones, DA, Van-Eijl, TJ, Tsang, H, Warren, H, Hamshere, SM, Kapil, V, Jain, AK, Deaner, A, Poulter, N, et al
BMJ open. 2016;(12):e012728
Abstract
INTRODUCTION The mainstay treatment for reducing the symptoms of angina and long-term risk of heart attacks in patients with heart disease is stent implantation in the diseased coronary artery. While this procedure has revolutionised treatment, the incidence of secondary events remains a concern. These repeat events are thought to be due, in part, to continued enhanced platelet reactivity, endothelial dysfunction and ultimately restenosis of the stented artery. In this study, we will investigate whether a once a day inorganic nitrate administration might favourably modulate platelet reactivity and endothelial function leading to a decrease in restenosis. METHODS AND DESIGN NITRATE-OCT is a double-blind, randomised, single-centre, placebo-controlled phase II trial that will enrol 246 patients with stable angina due to have elective percutaneous coronary intervention procedure with stent implantation. Patients will be randomised to receive 6 months of a once a day dose of either nitrate-rich beetroot juice or nitrate-deplete beetroot juice (placebo) starting up to 1 week before their procedure. The primary outcome is reduction of in-stent late loss assessed by quantitative coronary angiography and optical coherence tomography at 6 months. The study is powered to detect a 0.22±0.55 mm reduction in late loss in the treatment group compared with the placebo group. Secondary end points include change from baseline assessment of endothelial function measured using flow-mediated dilation at 6 months, target vessel revascularisation (TVR), restenosis rate (diameter>50%) and in-segment late loss at 6 months, markers of inflammation and platelet reactivity and major adverse cardiac events (ie, myocardial infarction, death, cerebrovascular accident, TVR) at 12 and 24 months. ETHICS AND DISSEMINATION The study was approved by the Local Ethics Committee (15/LO/0555). Trial results will be published according to the CONSORT statement and will be presented at conferences and reported in peer-reviewed journals. TRIAL REGISTRATION NUMBERS NCT02529189 and ISRCTN17373946, Pre-results.
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Electron cryotomography reveals ultrastructure alterations in platelets from patients with ovarian cancer.
Wang, R, Stone, RL, Kaelber, JT, Rochat, RH, Nick, AM, Vijayan, KV, Afshar-Kharghan, V, Schmid, MF, Dong, JF, Sood, AK, et al
Proceedings of the National Academy of Sciences of the United States of America. 2015;(46):14266-71
Abstract
Thrombocytosis and platelet hyperreactivity are known to be associated with malignancy; however, there have been no ultrastructure studies of platelets from patients with ovarian cancer. Here, we used electron cryotomography (cryo-ET) to examine frozen-hydrated platelets from patients with invasive ovarian cancer (n = 12) and control subjects either with benign adnexal mass (n = 5) or free from disease (n = 6). Qualitative inspections of the tomograms indicate significant morphological differences between the cancer and control platelets, including disruption of the microtubule marginal band. Quantitative analysis of subcellular features in 120 platelet electron tomograms from these two groups showed statistically significant differences in mitochondria, as well as microtubules. These structural variations in the platelets from the patients with cancer may be correlated with the altered platelet functions associated with malignancy. Cryo-ET of platelets shows potential as a noninvasive biomarker technology for ovarian cancer and other platelet-related diseases.
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Antiplatelet effect of clopidogrel can be reduced by calcium-channel blockers.
Seo, KD, Kim, YD, Yoon, YW, Kim, JY, Lee, KY
Yonsei medical journal. 2014;(3):683-8
Abstract
PURPOSE Clopidogrel is metabolized by the hepatic cytochrome P450 (CYP) system into its active thiol metabolite. CYP3A4 is involved in the metabolism of both clopidogrel and dihydropyridine calcium channel blockers (CCBs). A few reports have suggested an inhibitory interaction between CCBs and clopidogrel. Accordingly, the aim of this study was to determine the effect of CCBs on the antiplatelet activity of clopidogrel by serial P2Y12 reaction unit (PRU) measurements. MATERIALS AND METHODS We assessed changes in antiplatelet activity in patients receiving both clopidogrel and CCBs for at least 2 months prior to enrollment in the study. The antiplatelet activity of clopidogrel was measured by VerifyNow P2Y12 assay in the same patient while medicated with CCBs and at 8 weeks after discontinuation of CCBs. After discontinuation of the CCBs, angiotensin receptor blockers were newly administered to the patients or dosed up for control of blood pressure. RESULTS Thirty patients finished this study. PRU significantly decreased after discontinuation of CCBs (238.1±74.1 vs. 215.0±69.3; p=0.001). Of the 11 patients with high post-treatment platelet reactivity to clopidogrel (PRU≥275), PRU decreased in nine patients, decreasing below the cut-off value in seven of these nine patients after 8 weeks. Decrease in PRU was not related to CYP2C19 genotype. CONCLUSION CCBs inhibit the antiplatelet activity of clopidogrel.
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Atypical erythrocytes and platelets in a patient with a pro-thrombin mutation.
Pretorius, E, Vermeulen, N, Bester, J
Platelets. 2014;(6):461-2
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Abstract
Prothrombin mutation G20210A, anti-phospholipid syndrome as well as iron overload has previously been shown to cause thrombotic events. The main reason for this is the involvement of these anomalies in causing hypercoagulability of the coagulation system, which frequently leads to venous and arterial thrombotic events. We report the case of a 37-year-old white female with prothrombin mutation G20210A, anti-phospholipid syndrome, as well as an increased serum ferritin level, who experienced two transient ischemic attacks and suffers from regular amaurosis fugax. We present an ultrastructural depiction of erythrocytes, platelets, and the fibrin network, to explain the clinical manifestations of the thrombotic state seen in this patient.
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Identification of the thiol isomerase-binding peptide, mastoparan, as a novel inhibitor of shear-induced transforming growth factor β1 (TGF-β1) activation.
Brophy, TM, Coller, BS, Ahamed, J
The Journal of biological chemistry. 2013;(15):10628-39
Abstract
TGF-β1 is a disulfide-bonded homodimeric protein produced by platelets and other cells that plays a role in many physiologic and pathologic processes. TGF-β1 is secreted as an inactive large latent complex (LLC) comprised of TGF-β1, latency-associated peptide, and latent TGF-β binding protein 1. We previously demonstrated that shear force can activate LLC and that thiol-disulfide exchange contributes to the process. We have now investigated the role of thiol isomerases in the activation of LLC in platelet releasates (PR) and recombinant LLC. The wasp venom peptide mastoparan, which inhibits the chaperone activity of PDI, inhibited stirring- and shear-induced activation of latent TGF-β1 by 90 and 75% respectively. To identify the proteins that bind to mastoparan either directly or indirectly, PR were chromatographed on a mastoparan affinity column. Latent TGF-β binding protein 1, latency-associated peptide, TGF-β1, clusterin, von Willebrand factor, multimerin-1, protein disulfide isomerase (PDI), ERp5, ERp57, and ERp72 eluted specifically from the column. Anti-PDI RL90 attenuated the inhibitory effect of mastoparan on LLC activation. Furthermore, reduced PDI inhibited activation of PR LLC, whereas oxidized PDI had no effect. We conclude that thiol isomerases and thiol-disulfide exchange contribute to TGF-β1 activation and identify a number of molecules that may participate in the process.
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Skin bleeding time for the evaluation of uremic platelet dysfunction and effect of dialysis.
Soyoral, YU, Demir, C, Begenik, H, Esen, R, Kucukoglu, ME, Aldemir, MN, Demirkiran, D, Erkoc, R
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2012;(2):185-8
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Abstract
INTRODUCTION In patients with chronic kidney disease (CKD) predisposition to bleeding is frequently seen due to disturbances in platelet adhesion and aggregation. Various tests have been utilized to evaluate the disturbance of hemostasis in end-stage renal disease patients. In this trial; we evaluated skin bleeding time in patients admitted to our hospital with uremic symptoms and having hemodialysis (HD) for the first time. We also examined the effects of HD and uremia on this test and investigated its effectiveness in predicting the hemorrhagic complications before implementation of invasive procedures in uremic patients. MATERIAL-METHOD Twenty nine patients (13 men,16 women; mean age 59.7 ± 18.1) with CKD who presented with symptoms of uremia and treated with HD for the first time were enrolled in this trial. The skin bleeding time were measured before initiation of first hemodialysis and after the second hemodialysis session. RESULTS The skin bleeding time after the second dialysis was significantly shorter when compared to pre-dialysis values (p < 0.05). Correlation analysis between the skin bleeding time and urea, creatinine, hemoglobin, platelet, and bicarbonate showed no correlation. CONCLUSIONS Skin bleeding time could reveal the uremic platelet dysfunction and beneficial effect of dialysis in the patients who presented with uremic symptoms and treated with HD for the first time. We suggest that skin bleeding time may be an appropriate test for the evaluation of hemostasis disturbance in uremic patients and prediction of the bleeding risk before invasive procedures.
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Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: recommendations to minimize the functional consequences.
Anzellotti, P, Capone, ML, Jeyam, A, Tacconelli, S, Bruno, A, Tontodonati, P, Di Francesco, L, Grossi, L, Renda, G, Merciaro, G, et al
Arthritis and rheumatism. 2011;(3):850-9
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OBJECTIVE To investigate whether low-dose naproxen sodium (220 mg twice a day) interferes with aspirin's antiplatelet effect in healthy subjects. METHODS We performed a crossover, open-label study in 9 healthy volunteers. They received for 6 days 3 different treatments separated by 14 days of washout: 1) naproxen 2 hours before aspirin, 2) aspirin 2 hours before naproxen, and 3) aspirin alone. The primary end point was the assessment of serum thromboxane B(2) (TXB(2)) 24 hours after the administration of naproxen 2 hours before aspirin on day 6 of treatment. In 5 volunteers, the rate of recovery of TXB(2) generation (up to 72 hours after drug discontinuation) was assessed in serum and in platelet-rich plasma stimulated with arachidonic acid (AA) or collagen. RESULTS Twenty-four hours after the last dosing on day 6 in volunteers receiving aspirin alone or aspirin before naproxen, serum TXB(2) was almost completely inhibited (median [range] 99.1% [97.4-99.4%] and 99.1% [98.0-99.7%], respectively). Naproxen given before aspirin caused a slightly lower inhibition of serum TXB(2) (median [range] 98.0% [90.6-99.4%]) than aspirin alone (P = 0.0007) or aspirin before naproxen (P = 0.0045). All treatments produced a maximal inhibition of AA-induced platelet aggregation. At 24 hours, compared with baseline, collagen-induced platelet aggregation was still inhibited by aspirin alone (P = 0.0003), but not by aspirin given 2 hours before or after naproxen. Compared with administration of aspirin alone, the sequential administration of naproxen and aspirin caused a significant parallel upward shift of the regression lines describing the recovery of platelet TXB(2). CONCLUSION Sequential administration of 220 mg naproxen twice a day and low-dose aspirin interferes with the irreversible inhibition of platelet cyclooxygenase 1 afforded by aspirin. The interaction was smaller when giving naproxen 2 hours after aspirin. The clinical consequences of these 2 schedules of administration of aspirin with naproxen remain to be studied in randomized clinical trials.
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Sustained platelet-sparing effect of weekly low dose paclitaxel allows effective, tolerable delivery of extended dose dense weekly carboplatin in platinum resistant/refractory epithelial ovarian cancer.
Sharma, R, Graham, J, Blagden, S, Gabra, H
BMC cancer. 2011;:289
Abstract
BACKGROUND Platinum agents have shown demonstrable activity in the treatment of patients with platinum resistant, recurrent ovarian cancer when delivered in a "dose-dense" fashion. However, the development of thrombocytopenia limits the weekly administration of carboplatin to no greater than AUC 2. Paclitaxel has a well-described platelet sparing effect however its use to explicitly provide thromboprotection in the context of dose dense carboplatin has not been explored. METHODS We treated seven patients with platinum resistant ovarian cancer who had previously received paclitaxel or who had developed significant peripheral neuropathy precluding the use of further full dose weekly paclitaxel. RESULTS We were able to deliver carboplatin AUC 3 and paclitaxel 20 mg/m2 with no thrombocytopenia or worsening of neuropathic side-effects, and with good activity. CONCLUSIONS We conclude that this regimen may be feasible and active, and could be formally developed as a "platinum-focussed dose-dense scaffold" into which targeted therapies that reverse platinum resistance can be incorporated, and merits further evaluation.