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The purpose of this study was to evaluate associations between INNOVANCE PFA P2Y (PFA P2Y) test results and CYP2C19 genotypes and provide baseline data for PFA P2Y testing to establish a therapeutic monitoring strategy for clopidogrel. A total of 75 new patients with acute coronary syndrome with planned percutaneous coronary intervention were enrolled between June 2012 and September 2012. All patients received clopidogrel at an initial loading dose of 600?mg followed by a 75-mg daily maintenance dose. Blood samples were obtained on the third morning after clopidogrel loading. PFA P2Y, VerifyNow P2Y12 and VASP assays were used to determine platelet inhibition due to clopidogrel, and the Verigene CYP2C19 test was used for CYP2C19 genotyping. The genotype frequency of 75 patients was as follows: CYP2C19 *1/*1 (wild type), 28 (37.3%); *1/*2, 31 (41.3%); *1/*3, 4 (5.3%); *2/*2, 5 (6.7%); *2/*3, 5 (6.7%); *1/*17, 1 (1.3%); and *2/*17, 1 (1.3%). Classified according to CYP2C19 genotypes, there were 29 (38.7%) extensive metabolizers (EM) or ultra rapid metabolizers (UM), 35 (46.7%) intermediate metabolizers (IM), and 10 (13.3%) poor metabolizers (PM). Median (interquartile range) PFA P2Y closure times (seconds) were 119 (101–260), 300 (130–300) and 300 (300–300) in the PM, IM and EM or UM groups, respectively (p?<?0.05). Median (interquartile range) VerifyNow PRUs were 294 (213–297), 215 (165–320) and 189 (118–279); and the VASP platelet reactivity index (%) was 52.7 (33.3–91.9), 59.9 (41.4–72.8) and 38.9 (26.8–62.2) in the PM, IM and EM or UM groups, respectively (p?>?0.05). Compared with non-carriers, carriers of reduced function CYP2C19 alleles tended to have higher platelet reactivity after clopidogrel treatment. The cut-off for PM versus other groups (IM and EM or UM) was ≤141 seconds (AUC 0.704, sensitivity 70%, specificity 76.6%) on the ROC curve. A statistically significant correlation between PFA P2Y (seconds) and VerifyNow (PRU) was found (ρ?=??0.47, p?<?0.0001). In conclusion, the PFA P2Y test showed a statistically significant association with CYP2C19 metabolizer phenotypes based on CYP2C19 genotyping and effectively determined the risk groups resistant to clopidogrel therapy, including PM. 相似文献
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Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator‐stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry 下载免费PDF全文
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《Platelets》2013,24(6):421-428
Peroxynitrite is a potent nitrating and oxidizing agent that exerts differential effects on platelets. In the present study we investigated the influence of peroxynitrite on vasodilator-stimulated phosphoprotein (VASP), a protein that plays a key role in inhibition of platelet adhesion and spreading. In platelets, VASP is a substrate for protein kinase A (PKA), PKC and PKG and phosphorylation by these kinases is thought to block VASP-mediated actin cytoskeletal rearrangement. In the present study, we demonstrate that peroxynitrite phosphorylates VASP by a PKC-dependent mechanism. Peroxynitrite (0–100 µM) induced a concentration and time-dependent increase in phosphorylation of VASP at serine157 (Ser157) and Ser239. Inhibition of soluble guanylyl cyclase (sGC) did not significantly reduce peroxynitrite-mediated phosphorylation, indicating a cGMP-independent pathway for VASP phosphorylation. In contrast nitric oxide-mediated VASP phosphorylation was abolished under conditions of sGC inhibition. Further exploration of the mechanisms underlying VASP phosphorylation indicated a requirement for Ca2+ mobilization, but was independent of protein kinase A, Src kinases and protein nitration. Consistent with previous reports phorbol 12-myristate 13-acetate (PMA; 300 nM) induced phosphorylation of VASP at Ser157, but not Ser239, which was blocked by general protein kinase C (PKC) inhibitors, Ro31-8220 and Bisindolylmaleimide I (BIM-1), and Gö6976, an inhibitor of conventional PKC isoforms. Interestingly, treatment of platelets with these PKC inhibitors significantly reduced peroxynitrite-mediated phosphorylation of both sites, indicating that phosphorylation occurred through PKC-dependent mechanism. Consistent with these findings peroxynitrite caused a small increase in PKC activity as evidenced by increased phosphorylation of PKC substrates. Together these data indicate that peroxynitrite may inhibit platelet function by inducing the phosphorylation of VASP through a mechanism that requires the activation of PKC. 相似文献
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Joseph A. Jakubowski Dominick J. Angiolillo Chunmei Zhou David S. Small Brian A. Moser Jurrien M. ten Berg Patricia B. Brown Stefan James Kenneth J. Winters David Erlinge 《Thrombosis research》2014
Introduction
Patients treated with clopidogrel who have higher body size exhibit greater platelet reactivity than patients with lower body size. In a retrospective analysis of the FEATHER trial, we examined the relationship between platelet response to thienopyridines clopidogrel 75 mg (Clop-75), prasugrel 5 mg (Pras-5), and prasugrel 10 mg (Pras-10) using 3 body size indices: body weight (BW), body mass index (BMI), and body surface area (BSA). Relationships were assessed as continuous variables and as 4 incremental body size groups.Materials and Methods
Aspirin-treated patients with stable coronary artery disease (N = 72) and a BW range of 45-134 kg received Clop-75, Pras-5, and Pras-10 in a 3-period, blinded, cross-over study. Platelet assays included maximum platelet aggregation (MPA) to 20 μM ADP by light transmission aggregometry, VerifyNow-P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). Exposure to active metabolites (AMs) was also assessed.Results
Body size was a determinant of AM exposure and residual platelet reactivity regardless of type and dose of thienopyridine. BW and BSA demonstrated marginally stronger correlations with platelet reactivity; VASP-PRI demonstrated a stronger correlation with the body size than the other tests. Correlation coefficients ranged from a high of 0.64 (BW vs. PRI on Pras-5) to a low of 0.34 (BMI vs. MPA on Pras-10), but all were statistically significant (p < 0.01).Conclusions
Using a comprehensive selection of body size indices, AM exposures, platelet function tests, and thienopyridine doses, we demonstrated a consistent inverse relationship between body size and response to clopidogrel and prasugrel. 相似文献6.
Marc Laine Richard Toesca Julie Berbis Corinne Frere Pierre Barnay Michel Pansieri Jean-Pascal Peyre Pierre Michelet Jacques Bessereau Elise Camilleri Olfa Helaf Marjorie Camaleonte Franck Paganelli Françoise Dignat-George Laurent Bonello 《Thrombosis research》2013
Background
The level of platelet reactivity (PR) inhibition obtained after P2Y12-ADP receptor antagonist loading dose (LD) is associated with the ischemic and bleeding risk following percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS).Objective
We aimed to evaluate the level of PR inhibition achieved by a 180 mg LD of ticagrelor and the rate of high on-treatment platelet reactivity (HTPR) in ACS patients undergoing PCI.Methods
We performed a multicentre prospective observational study enrolling ACS patients undergoing PCI. Patients were included if they were admitted for ST-elevation myocardial infarction or non ST-elevation ACS. To assess PR, a VASP index was measured at least 6 and within 24 hours following a 180 mg LD of ticagrelor. HTPR was defined as a VASP index ≥ 50%.Results
One hundred and fifteen patients were included: 31.3% of STEMI, 49.6% of NSTEMI and 19.1% of unstable angina. Following ticagrelor LD the mean VASP index was 17 ± 14%. However the response to ticagrelor was not uniform with a small inter-individual variability: inter quartile range: 7.6–22.8% and a rate of HTPR of 3.5%. A high number of patients, 65.6%, had a VASP index < 16%. None of the baseline characteristics of the study population was associated with PR. In addition, PR was similar in STEMI, NSTEMI and unstable angina (p = 0.9).Conclusion
In ACS patients the level of PR inhibition achieved by a 180 mg loading dose of ticagrelor is not uniform and the rate of HTPR is 3.5%. A high proportion of patients exhibited a VASP index < 16%. 相似文献7.
Brandon Davis Jun Tang Li Zhang Dezhi Mu Xiangning Jiang Valerie Biran Zinaida Vexler Donna M. Ferriero 《International journal of developmental neuroscience》2010
The blood–brain barrier (BBB) plays an important role in the pathophysiology of central nervous system (CNS) disorders such as stroke and hypoxic–ischemic brain injury. Vascular endothelial growth factor (VEGF) is involved in angiogenesis and vasogenic edema during stroke and hypoxia. However, the role of VEGF in BBB permeability after hypoxia has not been fully elucidated. We therefore investigated VEGF effects in an in vitro BBB model using rbcec4 endothelial cell line with the stimulation of VEGF or hypoxia. In this study, BBB permeability was studied using 14C-sucrose detection. The expression of BBB tight junction protein ZO-1, and the expression and phosphorylation of vasodilator stimulated phosphoprotein (VASP), VEGF and VEGF receptor 2 (VEGFR2) were determined using fluorescent immunocytochemistry and western blot analyses. We found that hypoxia upregulated VEGF expression, and VEGF increased BBB permeability. Hypoxia also increased VASP phosphorylation, which was mediated, in part, through VEGFR2. We also found that VASP at tight junctions was co-localized with ZO-1 in cell–cell contacts. Our findings show that VASP phosphorylation is affected by hypoxia and VEGFR2 inhibition suggesting a role for VASP in BBB permeability. 相似文献
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稳定层流剪应力对内皮细胞骨架调节蛋白VASP表达的影响 总被引:1,自引:0,他引:1
为探讨生理强度的稳定层流剪应力对内皮细胞骨架actin相关蛋白VASP特征影响规律,我们采用胰蛋白酶消化法分离人脐静脉内皮细胞(HUVECs),模拟体内流动环境,建立平行板流动腔模型。利用细胞图像分析系统和ALEXA488—若丹明一次毒蕈环肽双标记法,观察内皮细胞在稳态层流下形态、actin排列变化与VASP分布变化之间的规律。采用Western blot定量动态检测细胞内VASP表达及磷酸化的水平。结果表明,内皮细胞在10dyn/cm^2剪切作用后,随时间细胞逐渐延长,长轴趋于剪应力作用方向排列,细胞与静息态的细胞相比,细胞内骨架沿剪应力方向重组,与此同时VASP表达增强,沿着actin纤维呈点状分布,尤其集中在细胞膜下actin末端区域;Western blot检测显示在剪切后,细胞内VASP出现快速磷酸化,VASP总体表达量增加,2h达高峰后逐渐恢复,8h后再次逐渐升高。以上结果提示血流动力学特性中剪应力引起了细胞胞质内骨架蛋白分子重组,血管内皮细胞形态改变,在此过程中,VASP发挥骨架调节蛋白的作用。 相似文献
9.
Tullio Palmerini Chiara Barozzi Diego Sangiorgi Stefano De Servi Letizia Bacchi Reggiani Giulia Lauria Angelo Branzi 《Thrombosis research》2010,125(4):309-314
Introduction
The antiplatelet effect of standard or increased clopidogrel doses in patients with ST- segment elevation acute myocardial infarction (STEMI) has never been studied. In this study we compared the antiplatelet effect of a 75 mg daily maintenance dose of clopidogrel with 150 mg in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).Materials and methods
Fifty-four patients with STEMI undergoing PCI were randomly allocated to receive either 75 mg/day clopidogrel (group 1) or 150 mg/day (group 2) for 1 month. Platelet function, measured by 5 different assays, was determined at 3 time points: 38 ± 8 hours after the procedure, 1 week and 1 month after randomization.Results
In group 1, mean ± SD platelet reactivity index (PRI) measured with the VASP assay was 57.7 ± 15.7% and 46.9 ± 15.7% at 1 week and 1 month, respectively, compared to 38.8 ± 15.7% and 34.9 ± 12.6% in group 2 (p = 0.0001). Same results were observed for light transmittance aggregometry, whole blood aggregometry and VerifyNow, but not for thromboelastometry. In contrast to what may be expected, the 75 mg daily maintenance dose took longer than 1-week to provide the full clopidogrel antiplatelet effect. Furthermore, patients in group 2 had a nearly 50% reduction in C-reactive protein levels both at 1 week and 1 month.Conclusion
In patients with STEMI and poor responsiveness to clopidogrel a 150 mg daily maintenance dose of clopidogrel is associated with a significant reduction of platelet aggregation and a trend towards reduced inflammation. 相似文献10.
Jochem W. van Werkum Heleen J. Bouman Nicoline J. Breet Jurriën M. ten Berg Christian M. Hackeng 《Thrombosis research》2010,126(1):44-49