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1.
Acute supplementation with eicosapentaenoic acid reduces platelet microparticle activity in healthy subjects.
Phang, M, Lincz, L, Seldon, M, Garg, ML
The Journal of nutritional biochemistry. 2012;(9):1128-33
Abstract
BACKGROUND Dietary supplementation with omega-3 fatty acids has been associated with reduced incidence in thrombotic events. In addition, administration of n-3 polyunsaturated fatty acids (PUFAs) has been shown to rectify elevated platelet microparticle (MP) number and procoagulant activity in post myocardial infarction patients. However, it is unknown whether supplementation can alter these parameters in healthy individuals and if such effects are immediate or require long-term supplementation. We have previously demonstrated a gender-specific effect of LCn-3PUFA supplementation on platelet aggregation in healthy human subjects. Here we extend these findings to include the acute effects of supplementation with EPA- or DHA-rich oils on circulating MP levels and activity in healthy subjects. DESIGN A placebo-controlled trial was conducted in healthy males and females (n=30). MP activity, MP levels and platelet aggregation were measured at 0 and 24 h postsupplementation with either a placebo or EPA- or DHA-rich oil. RESULTS Both EPA and DHA effectively reduced platelet aggregation at 24 h postsupplementation relative to placebo (-13.3%, P=.006 and -11.9%, P=.016, respectively), but only EPA reduced MP activity (-19.4%, P=.003). When grouped by gender, males showed a similar reduction in both platelet aggregation and MP activity (-20.5%, P=.008; -22%, P=.008) following EPA, while females showed significantly reduced platelet aggregation (-13.7%, P=.04) but not MP activity after DHA only. CONCLUSION EPA and DHA exert gender-dependent effects on platelet aggregation and platelet MP activity, but not on MP levels. With respect to thrombotic disease risk, males may benefit more from EPA supplementation.
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2.
In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin.
Russo, I, Traversa, M, Bonomo, K, De Salve, A, Mattiello, L, Del Mese, P, Doronzo, G, Cavalot, F, Trovati, M, Anfossi, G
Obesity (Silver Spring, Md.). 2010;(4):788-97
Abstract
Central obesity shows impaired platelet responses to the antiaggregating effects of nitric oxide (NO), prostacyclin, and their effectors--guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP). The influence of weight loss on these alterations is not known. To evaluate whether a diet-induced body-weight reduction restores platelet sensitivity to the physiological antiaggregating agents and reduces platelet activation in subjects affected by central obesity, we studied 20 centrally obese subjects before and after a 6-month diet intervention aiming at reducing body weight by 10%, by measuring (i) insulin sensitivity (homeostasis model assessment of insulin resistance (HOMA(IR))); (ii) plasma lipids; (iii) circulating markers of inflammation of adipose tissue and endothelial dysfunction, and of platelet activation (i.e., soluble CD-40 ligand (sCD-40L) and soluble P-selectin (sP-selectin)); (iv) ability of the NO donor sodium nitroprusside (SNP), the prostacyclin analog Iloprost and the cyclic nucleotide analogs 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) and 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) to reduce platelet aggregation in response to adenosine-5-diphosphate (ADP); and (v) ability of SNP and Iloprost to increase cGMP and cAMP. The 10 subjects who reached the body-weight target showed significant reductions of insulin resistance, adipose tissue, endothelial dysfunction, and platelet activation, and a significant increase of the ability of SNP, Iloprost, 8-Br-cGMP, and 8-Br-cAMP to reduce ADP-induced platelet aggregation and of the ability of SNP and Iloprost to increase cyclic nucleotide concentrations. No change was observed in the 10 subjects who did not reach the body-weight target. Changes of platelet function correlated with changes of HOMA(IR). Thus, in central obesity, diet-induced weight loss reduces platelet activation and restores the sensitivity to the physiological antiaggregating agents, with a correlation with improvements in insulin sensitivity.
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3.
Efficacy of clopidrogel on reperfusion and high-sensitivity C-reactive protein in patients with acute myocardial infarction.
Akbulut, M, Kutlu, M, Ozbay, Y, Polat, V, Bilen, MN, Baydas, A, Altas, Y
Mediators of inflammation. 2009;:932515
Abstract
We investigated the effects of clopidogrel on reperfusion and inflammatory process in STEMI. A total of 175 STEMI patients with similar clinical characteristics were included to this study. One was the standard pharmacological reperfusion therapy group (group 1, n : 90), who received 300 mg aspirin, 70 U/kg bolus, and 12 U/kg/hr continuous infusion of unfractioned heparin and accelerated t-PA. Clopidogrel 450 mg loading and 75 mg/d thereafter was added to standard reperfusion therapy in the other group (group 2, n : 85). The ST-segment resolution, CK-MB, and high-sensitive CRP (hs-CRP) parameters were measured. Complete ST resolution was observed in 32 patients (36.8%) in group 1 and 53 patients (63.8%) in group 2 (P < .001). Also in the first 24 hours, the CK-MB levels of patients in group 1 were significantly higher than those of group 2 (P = .001). The hs-CRP values were greater in group 1 than group 2 at 48th hour (group 1: 9.4 +/- 0.1 mg/L, group 2: 3.7 +/- 1.4 mg/L; P = .000). We concluded that adding clopidogrel to standard treatment in STEMI patients provided early reperfusion and suppression of inflammatory response.
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Antiplatelet response to the 150-mg maintenance dose of clopidogrel in patients with insufficient platelet inhibition after clopidogrel loading for elective coronary stent placement.
Trenk, D, Hochholzer, W, Müller, B, Stratz, C, Valina, CM, Schmiebusch, P, Büttner, HJ, Neumann, FJ
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2008;(2):214-21
Abstract
AIMS: Our prospective study sought to investigate whether inadequate platelet responses to clopidogrel can be corrected by increasing the daily maintenance dose from 75 mg to 150 mg. METHODS AND RESULTS In 117 patients with elective PCI after loading with 600 mg clopidogrel, we determined residual platelet aggregation in response to 5 micromol/l ADP (RPA) by optical aggregometry after the first 75 mg maintenance dose (baseline), and at days 14 and 28. In patients with RPA >14% at baseline, we increased the daily dose to 150 mg. Fifty-seven additional patients without dose adjustment served as historic control. In 39 patients with baseline RPA >14%, the increase in maintenance dose to 150 mg reduced median RPA significantly (P<0.001) from 24% [interquartile range: 18-32%] at baseline to 14% [8-20%1 at 14 days without any further significant change. In patients with RPA < or = 14%, who continued on 75 mg clopidogrel, RPA increased during the first 14 days by 4.5% (0-14%; P<0.001). At 14 days, the study group with selective dose adjustment had a significantly lower RPA than the control group without dose adjustment (10.0% [4-20%1 versus 17.0% [9-32%], P<0.001). CONCLUSIONS In patients with a low initial response to clopidogrel, platelet inhibition can be improved by increasing the maintenance dose to 150 mg.
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5.
Effects of Quyu Xiaoban capsules on clinical outcomes and platelet activation and aggregation in patients with unstable angina pectoris.
Liu, YF, Yu, HM, Zhang, C, Yang, RX, Yan, FF, Liu, Y, Zhang, Y, Zhao, YX
Journal of alternative and complementary medicine (New York, N.Y.). 2007;(5):571-6
Abstract
OBJECTIVES To investigate the effects of the Traditional Chinese Medicine (TCM) Quyu Xiaoban capsules (QYXB) on clinical outcomes and platelet activation and aggregation in patients with unstable angina pectoris (UAP) and phlegm and blood stasis syndrome. DESIGN Ninety (90) UAP patients were randomly divided into two groups: the control group received a loading dose of 300 mg aspirin and a maintenance dose of 100 mg of aspirin plus baseline therapy for 4 weeks, and the trial group received the same doses of aspirin and baseline therapy plus QYXB for 4 weeks. The severity of anginal attacks, alterations of TCM symptoms and signs, and electrocardiographic (ECG) changes were observed in all patients before and after treatment. Plasma platelet aggregation (PAG) rate and P-selectin level were measured in all patients at baseline and at the end of the fourth week. RESULTS After treatment for 4 weeks, both group of patients showed improvement in the severity of angina pectoris and TCM symptoms and signs, and there was a significant difference of the total effective rate in clinical improvement between the two groups, whereas no difference of the total effective rate in ECG improvement between the two groups was found. Compared with the baseline level, PAG rate in both groups decreased significantly at the end of the fourth week (63.74 +/- 11.18% versus 55.69 +/- 10.40 % in the control group, and 63.83 +/- 12.70% versus 50.04 +/- 8.91% in the trial group). Similar changes of P-selectin levels were observed in both groups (9.40 +/- 1.25 ng/mL versus 8.90 +/- 1.34 ng/mL in the control group and 9.56 +/- 1.16 ng/mL versus 7.80 +/- 0.98 ng/mL in the trial group). However, both PAG rate and P-selectin level decreased to a greater extent in the trial group than in the control group after treatment, and the difference between treatment was significant (both p<0.05). Nevertheless, these biochemical changes were too small to explain fully the beneficial clinical outcomes achieved by QYXB capsules. CONCLUSIONS On the background of baseline and aspirin therapy, QYXB capsules significantly attenuated anginal attacks and improved TCM symptoms and signs in patients with UAP, and the exact mechanisms underlying these therapeutic effects remain to be explored.
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6.
Effects of Quyu xiaoban capsules on clinical outcomes and platelet activation and aggregation in patients with unstable angina pectoris.
Liu, YF, Yu, HM, Zhang, C, Yang, RX, Yan, FF, Liu, Y, Zhang, Y, Zhao, YX
Journal of alternative and complementary medicine (New York, N.Y.). 2007;(3):369-74
Abstract
OBJECTIVES To investigate the effects of the Traditional Chinese Medicine (TCM) Quyu Xiaoban capsules (QYXB) on clinical outcomes and platelet activation and aggregation in patients with unstable angina pectoris (UAP) and phlegm and blood stasis syndrome. DESIGN Ninety patients with UAP were randomly divided into two groups: a control group that received a loading dose of 300 mg aspirin and a maintenance dose of 100 mg of aspirin plus baseline therapy for 4 weeks, and a trial group that received the same doses of aspirin and baseline therapy plus QYXB for 4 weeks. The severity of anginal attacks, alterations of TCM symptoms and signs, and electrocardiographic (ECG) changes were assessed in all patients before and after treatment. The plasma platelet aggregation (PAG) rate and P-selectin level were measured in all patients at baseline and at the end of the fourth week of treatment. RESULTS After treatment for 4 weeks, both group of patients showed improvement in the severity of angina pectoris and TCM symptoms and signs, but there was a significant difference in the two groups' rates of clinical improvement, whereas the rate of ECG improvement of the two groups showed no difference. As compared with the baseline value, the PAG rate in both groups decreased significantly at the end of the fourth week (63.74 +/- 11.18% vs. 55.69 +/- 10.40% in the control group, and 63.83 +/- 12.70% vs. 50.04 +/- 8.91% in the trial group). Similar changes in P-selectin levels were observed in the two groups (9.40 +/- 1.25 ng/mL vs. 8.90 +/- 1.34 ng/mL in the control group, and 9.56 +/- 1.16 ng/mL vs. 7.80 +/- 0.98 ng/mL in the trial group). However, both the PAG rate and P-selectin level decreased to a greater extent in the trial group than in the control group after treatment, and the difference between the two groups was significant (both p < 0.05). Nevertheless, these biochemical changes were too small to fully explain the beneficial clinical outcomes achieved with QYXB capsules. CONCLUSIONS In comparison with both the respective baseline values and with aspirin therapy, QYXB capsules significantly attenuated anginal attacks and improved TCM symptoms and signs in patients with UAP. The exact mechanisms underlying these therapeutic effects remain to be explored.
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7.
Effects of diltiazem on platelet activation and cytosolic calcium during percutaneous transluminal coronary angioplasty.
Dai, H, Chen, J, Tao, Q, Zhu, J, Zhang, F, Zheng, L, Qiu, Y
Postgraduate medical journal. 2003;(935):522-6
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Abstract
AIMS: To evaluate effects of diltiazem on platelet hyper-reactivity in situations associated with endothelial injury and their possible relationship to cytosolic calcium concentration. METHODS Blood samples were collected at seven time points from 35 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) who received combined diltiazem and aspirin/ticlopidine therapy or aspirin/ticlopidine therapy alone. Platelet expression of glycoprotein IIb/IIIa and P-selectin, production of thromboxane B(2), and cytosolic calcium concentration were measured, respectively, by whole blood flow cytometry, radioimmunoassay, and fluorospectrophotometry. The effects of diltiazem of different concentrations on expression of glycoprotein IIb/IIIa and P-selectin were also studied in vitro in blood samples from patients with chronic stable angina. RESULTS Of the two treatments, aspirin/ticlopidine therapy did not prevent an acute increase of expression of glycoprotein IIb/IIIa and P-selectin and plasma thromboxane B(2) five minutes and 10 minutes after first inflation and 10 minutes after PTCA, whereas combined diltiazem and aspirin/ticlopidine therapy had a significant inhibitory effect. In the group receiving aspirin/ticlopidine therapy, there was a short term increase of platelet [Ca(2+)](i) immediately after PTCA which was significantly reduced by diltiazem treatment. Expression of glycoprotein IIb/IIIa and P-selectin was significantly inhibited in vitro by diltiazem in the concentration of 200 ng/ml or higher, but not 50 ng/ml. CONCLUSIONS Combined diltiazem and aspirin/ticlopidine therapy significantly inhibited platelet activation that continued in the presence of conventional aspirin/ticlopidine treatment. Antiplatelet effects of diltiazem were probably a consequence of reduction of platelet [Ca(2+)](i) and may only be achieved in higher than therapeutic concentrations.
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The effect of IM ketorolac tromethamine on bleeding time: a prospective, interventional, controlled study.
Singer, AJ, Mynster, CJ, McMahon, BJ
The American journal of emergency medicine. 2003;(5):441-3
Abstract
Opiates, although effective analgesics, have significant adverse side effects. Ketorolac, the only parental nonsteroidal antiinflammatory drug available for use in the United States does not cause significant respiratory depression or hypotension, but it is a reversible inhibitor of platelet aggregation with a theoretical increased bleeding risk, which limits its use. The objective of this study was to determine the effect of a single intramuscular dose of 60 mg ketorolac on 4-hour bleeding times in healthy volunteers. This was a prospective, paired, unblinded, before-and-after interventional study performed in a suburban university-based EM residency training program. Subjects were 20 healthy volunteer EM residents. Standard Ivy bleeding times were measured before and 4 hours after intramuscular administration of 60 mg ketorolac. Before-and-after bleeding times were compared using a paired t-test. The study had 90% power to detect an effect size of 0.5. The subjects' mean age was 31.6 and 7 (35%) were females. Bleeding time was increased from a mean baseline time of 3 minutes 34 seconds (+/- 1 min 20 sec) to a mean 4-hour postinjection time of 5 minutes 20 seconds (+/- 3 min 8 sec). The mean prolongation of bleeding time was 1 minute 46 seconds (50% increase with 95% confidence interval, 25%-75%). There were no adverse events. A standard intramuscular dose of 60 mg ketorolac resulted in prolongation of the bleeding time in healthy volunteers. The clinical significance of this prolongation in patients is unclear.
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Effect of abciximab on cardiac enzyme elevation after transluminal extraction atherectomy (TEC) in high-risk saphenous vein graft lesions: comparison with a historical control group.
Khan, MA, Liu, MW, Chio, FL, Yates, VB, Chapman, GD, Misra, VK, Sweeney, A, Dean, LS
Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2001;(1):40-4
Abstract
Saphenous vein graft (SVG) intervention has been associated with an increased incidence of distal embolization. Long lesions and lesions associated with thrombus are particularly at increased risk. This study was performed to determine whether abciximab may decrease this risk in high risk SVG angioplasty. From June 1994 to June 1998, 84 patients with at least one high risk factor, i.e., lesion length >20 mm or angiographic evidence of thrombus, underwent Transluminal extraction atherectomy (TEC) procedure followed by balloon dilatation or stenting. Of these 84 patients, 37 who had procedure after September 1995 underwent TEC with abciximab (Abciximab Group) and 47 who had their procedure before that date had TEC without abciximab thereby serving as historic control (Non-Abciximab Group). All patients had normal pre-procedure CK and CK-MB. Total creatine kinase (CK) and CK-MB were measured every 8 hr post-procedure for 24 hr. Baseline demographics, angiographic characteristics, incidence of LV dysfunction and triple vessel disease were similar between the two groups. Graft age was similar between two groups (122 +/- 70 vs. 117 +/- 54 months). Graft diameter, pre and post-procedure percent stenoses were not different between the two groups. Stents were used in 65% in the Abciximab group and 45% in Non-Abciximab group (P = 0. 14). There was no in-hospital repeat PTCA, urgent bypass surgery, or cardiac death. There was no difference between the two groups in regards to the incidence of any elevation of total CK (27% vs. 21. 3%) or CK-MB (54% vs. 51%). When used in conjunction with TEC in treating high risk vein graft lesions, abciximab did not reduce post procedure CK-MB elevation in this patient population.
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A 4-trifluoromethyl derivative of salicylate, triflusal, stimulates nitric oxide production by human neutrophils: role in platelet function.
De Miguel, LS, Jiménez, A, Montón, M, Farré, J, Del Mar Arriero, M, Rodríguez-Feo, JA, García-Cañete, J, Rico, L, Gómez, J, Núñez, A, et al
European journal of clinical investigation. 2000;(9):811-7
Abstract
BACKGROUND The thrombotic process is a multicellular phenomenon in which not only platelets but also neutrophils are involved. Recent in vitro studies performed in our laboratory have demonstrated that triflusal, a 4-trifluoromethyl derivative of salicylate, reduced platelet aggregation not only by inhibiting thromboxane A2 production but also by stimulating nitric oxide (NO) generation by neutrophils. The aim of the present study was to evaluate whether oral treatment of healthy volunteers with triflusal could modify the ability of their neutrophils to produce NO and to test the role of the NO released by neutrophils in the modulation of ADP-induced platelet aggregation and alpha-granule secretion. METHODS The study was performed in 12 healthy volunteers who were orally treated with triflusal (600 mg day-1) for 5 days. Flow cytometric detection of platelet surface expression of P-selectin was used as a measure of the ability of platelets to release the contents of their alpha-granules. RESULTS After treatment with triflusal, there was an increase in NO production by neutrophils and an increase in endothelial nitric oxide synthase (eNOS) protein expression in neutrophils. A potentiation of the inhibition of platelet aggregation by neutrophils was reversed by incubating neutrophils with both an L-arginine antagonist, NG-nitro-L-arginine methyl ester (L-NAME) and an NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline 1-oxyl 3-oxide (C-PTIO). A slight decrease in P-selectin surface expression on platelets was found which was not modified by the presence of neutrophils and therefore by the neutrophil-derived NO. Exogenous NO released by sodium nitroprusside dose-dependently inhibited both ADP-stimulated alpha-granule secretion and platelet aggregation. Therefore, platelet aggregation showed a greater sensitivity to be inhibited by exogenous NO than P-selectin expression. CONCLUSION Oral treatment of healthy volunteers with triflusal stimulated NO production and eNOS protein expression in their neutrophils. After triflusal treatment, the neutrophils demonstrated a higher ability to prevent ADP-induced platelet aggregation. However, the neutrophils and the endogenous NO generated by them failed to modify P-selectin expression in ADP-activated platelets.