氯吡格雷抑制冠心病患者血小板活化的差异性研究
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摘要
阿司匹林和氯吡格雷对心血管疾病患者的抗血小板治疗是预防介入手术后缺血事件的一项重要而且被广泛使用的手段,然而,治疗效果具有较大的个体差异,如阿司匹林抵抗和支架内血栓等不良事件仍然发生率较高。为了明确诊断通常需要做很多检查,结果却令人困惑。在药物监测上,依旧缺乏能够区分血小板粘附、聚集、活化和释放功能的灵敏而特异的诊断试验。
本研究以服用阿司匹林的冠心病患者为受试对象,在连续两天分两次给予600mg氯吡格雷。由于没有形成广泛接受的应用标准来衡量抗血小板治疗的个体效果,临床上对于方法选择缺乏可靠依据。为此,我们选用了代表性的主流方法：血小板聚集率、血栓弹力图测定抑制率、流式细胞术测定的血小板表面活化标志物CD62p和P2Y,2受体,观察服用首次300mg负荷剂量氯吡格雷后10h和36h(累计600mg)血小板活化的抑制情况,比较不同途径反应的差异性和不同方法对这种差异性的表现特征。
针对导致个体差异的遗传学多态性、细胞学和方法学因素,选择了功能已知的CYP2C19*2(681G>A)和CYP2C19*3(636G>A)两个热点位点,以高分辨融合技术通过扩增直接筛查遗传变异。发现*2突变1例,未见*3突变,突变个体与野生型在多项检测指标上存在显著差异,如：用药前后ADP活化途径的抑制都低于5%。突变和野生型个体在首次300mg负荷剂量后10h都显示出的抑制效果,但是突变个体没有进一步表现出时间依赖效应,不仅药物转化代谢缓慢,而且血小板功能抑制效果减弱。600mg分两次服用的用药方式可能不足以产生强烈的抑制效果。心血管疾病的遗传学筛查尚未纳入临床常规检查,然而,其重要性关系到患者心血管事件复发与否的关键性问题。因此,开展主要功能缺陷性遗传突变的筛查对细化检验参考区间和优化治疗方案具有现实意义。除了热点突变与疗效关系之外,本研究还进行了基于液相色谱和质谱联用(LC-MS/MS)的血药浓度检测,分析药物浓度与多态性之间的关联。
研究表明：服用氯吡格雷后的血小板COX-1和ADP途径受到程度不同的抑制,而且在不同分析方法中有不同表现。缺乏评价标准将导致对血小板反应性认识的不一致,基于血栓弹力图的血小板抑制率在大大提高操作标准化和重现性的同时,真实地反映了血小板凝集活性在全血中的体现,但是其反应特征与聚集率并不相同。新型的舒血管刺激磷蛋白(VASP)磷酸化分析能够特异地反应血小板P2Y12受体的抑制,但是其变化趋势及不同于全血中的抑制率,也不同于另一个血小板膜活化标志物-CD62p。由于缺乏广泛认可的临床指南或专家共识,对于抗血小板治疗的临床监测,根据用药的类别选择方便而特异的技术手段更具有现实意义,一味进行方法学的相关分析将导致临床应用的误区。
药效学和关于血小板活性的转化型研究突显出当前口服抗血小板治疗的局限性,大规模临床试验所提出的千篇一律的治疗方案无疑妨碍个体化医疗的实现。治疗中血小板高活性将成为决定心血管病患者救治标准的主要风险因子,一方面,部分治疗中血小板反应过低的患者未必出血,另一方面高活性者可能缺血。鉴于此,开展治疗前的遗传学筛查,建立活化途径特异的检测方法及其标准有助于为临床治疗提供有价值的参考信息。
Dual antiplatelet treatment with aspirin and clopidogrel is a main and widely used therapy on patients with cardiovascular disease for preventing thrombosis of treated vessels and subsequent ischemic events. However, great individual variabilitis including aspirin resistance and stenting thrombosis can be found among patients treated. No sensitive and specific assay is available to screen any dysfunction in platelet adhesion, aggregation, activation and secretion. Although there is always no clear indication, several tests are necessary to evaluate platelet function. Factors from genetic polymorphism, cellular and methodology were considered in this study. Blood concentration of clopidogrel was measure with LC-MS/MS to verify the relation between drug concentration and polymorphism. Major tools such as platelet aggregation, inhibition on Thrombelastography, platelet memberane activating marker-CD62p and vasodilator sitmulated phosphoprotein (VASP) were applied to evaluated platelet function on different time point at baseline,10h and 36h after 300mg loading dose.
CYP2C19*2 (681G>A) and*3 (636G>A) were genotyped with High Resolution Melting, only one*2 mutation and no*3 were found. Subject with mutation is different with wild individuals on several parameters like ADP induced aggregation. Although both wild and mutation subject(s) were inhibited at 10h after 300mg loading dose, no further time depended effect was found in the mutation. In addition, it showed not only slow drug metabolism, but also decreasing inhibition. Therefore, dividing 600mg loading dose into two days may not achieve enough inhibition.
Genetic screening of risk factors have not become clinical routine test, however, polymorphism is important to recurrent of cardiovascular events in certain individual. Thus, screening of major functional mutation will lead to determination of reference range and optimization of therapy. Lack of criteria on platelet function analysis will lead to aberration judgement of platelet reaction, even clinical desicition. Platelet inhibition based on Thrombelastography improves reproducibility and standardization much more than aggregation, but the change of parameter is different from the latter. VASP phosphrilation could reflect inhibition of P2Y12 receptor secificly, no relation can be found between VASP and CD62p. As to monitoring on antiplatelet therapy, it is important to choose assays according drug intake, correlation analysis may not feasible to all method for different principle, even lead to wrong decision.
本研究以服用阿司匹林的冠心病患者为受试对象,在连续两天分两次给予600mg氯吡格雷。由于没有形成广泛接受的应用标准来衡量抗血小板治疗的个体效果,临床上对于方法选择缺乏可靠依据。为此,我们选用了代表性的主流方法：血小板聚集率、血栓弹力图测定抑制率、流式细胞术测定的血小板表面活化标志物CD62p和P2Y,2受体,观察服用首次300mg负荷剂量氯吡格雷后10h和36h(累计600mg)血小板活化的抑制情况,比较不同途径反应的差异性和不同方法对这种差异性的表现特征。
针对导致个体差异的遗传学多态性、细胞学和方法学因素,选择了功能已知的CYP2C19*2(681G>A)和CYP2C19*3(636G>A)两个热点位点,以高分辨融合技术通过扩增直接筛查遗传变异。发现*2突变1例,未见*3突变,突变个体与野生型在多项检测指标上存在显著差异,如：用药前后ADP活化途径的抑制都低于5%。突变和野生型个体在首次300mg负荷剂量后10h都显示出的抑制效果,但是突变个体没有进一步表现出时间依赖效应,不仅药物转化代谢缓慢,而且血小板功能抑制效果减弱。600mg分两次服用的用药方式可能不足以产生强烈的抑制效果。心血管疾病的遗传学筛查尚未纳入临床常规检查,然而,其重要性关系到患者心血管事件复发与否的关键性问题。因此,开展主要功能缺陷性遗传突变的筛查对细化检验参考区间和优化治疗方案具有现实意义。除了热点突变与疗效关系之外,本研究还进行了基于液相色谱和质谱联用(LC-MS/MS)的血药浓度检测,分析药物浓度与多态性之间的关联。
研究表明：服用氯吡格雷后的血小板COX-1和ADP途径受到程度不同的抑制,而且在不同分析方法中有不同表现。缺乏评价标准将导致对血小板反应性认识的不一致,基于血栓弹力图的血小板抑制率在大大提高操作标准化和重现性的同时,真实地反映了血小板凝集活性在全血中的体现,但是其反应特征与聚集率并不相同。新型的舒血管刺激磷蛋白(VASP)磷酸化分析能够特异地反应血小板P2Y12受体的抑制,但是其变化趋势及不同于全血中的抑制率,也不同于另一个血小板膜活化标志物-CD62p。由于缺乏广泛认可的临床指南或专家共识,对于抗血小板治疗的临床监测,根据用药的类别选择方便而特异的技术手段更具有现实意义,一味进行方法学的相关分析将导致临床应用的误区。
药效学和关于血小板活性的转化型研究突显出当前口服抗血小板治疗的局限性,大规模临床试验所提出的千篇一律的治疗方案无疑妨碍个体化医疗的实现。治疗中血小板高活性将成为决定心血管病患者救治标准的主要风险因子,一方面,部分治疗中血小板反应过低的患者未必出血,另一方面高活性者可能缺血。鉴于此,开展治疗前的遗传学筛查,建立活化途径特异的检测方法及其标准有助于为临床治疗提供有价值的参考信息。
Dual antiplatelet treatment with aspirin and clopidogrel is a main and widely used therapy on patients with cardiovascular disease for preventing thrombosis of treated vessels and subsequent ischemic events. However, great individual variabilitis including aspirin resistance and stenting thrombosis can be found among patients treated. No sensitive and specific assay is available to screen any dysfunction in platelet adhesion, aggregation, activation and secretion. Although there is always no clear indication, several tests are necessary to evaluate platelet function. Factors from genetic polymorphism, cellular and methodology were considered in this study. Blood concentration of clopidogrel was measure with LC-MS/MS to verify the relation between drug concentration and polymorphism. Major tools such as platelet aggregation, inhibition on Thrombelastography, platelet memberane activating marker-CD62p and vasodilator sitmulated phosphoprotein (VASP) were applied to evaluated platelet function on different time point at baseline,10h and 36h after 300mg loading dose.
CYP2C19*2 (681G>A) and*3 (636G>A) were genotyped with High Resolution Melting, only one*2 mutation and no*3 were found. Subject with mutation is different with wild individuals on several parameters like ADP induced aggregation. Although both wild and mutation subject(s) were inhibited at 10h after 300mg loading dose, no further time depended effect was found in the mutation. In addition, it showed not only slow drug metabolism, but also decreasing inhibition. Therefore, dividing 600mg loading dose into two days may not achieve enough inhibition.
Genetic screening of risk factors have not become clinical routine test, however, polymorphism is important to recurrent of cardiovascular events in certain individual. Thus, screening of major functional mutation will lead to determination of reference range and optimization of therapy. Lack of criteria on platelet function analysis will lead to aberration judgement of platelet reaction, even clinical desicition. Platelet inhibition based on Thrombelastography improves reproducibility and standardization much more than aggregation, but the change of parameter is different from the latter. VASP phosphrilation could reflect inhibition of P2Y12 receptor secificly, no relation can be found between VASP and CD62p. As to monitoring on antiplatelet therapy, it is important to choose assays according drug intake, correlation analysis may not feasible to all method for different principle, even lead to wrong decision.
引文
1 Gurbel PA, Tantry US. Selecting optimal antiplatelet therapy based on platelet function monitoring in patients with coronary artery disease. Curr Treat Options Cardiovasc Med 2009; 11:22-32
2 Caplain H, Donat F, Gaud C,et al. Pharmacokinetics of clopidogrel. S eminars in Thrombosis and Hemostasis,1999,25 (2):251
3 Gurbel PA, Becker RC, Mann KG, et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007,50:1822-1834.
4 Tantry US, Bliden KP,Gurbel PA. Overestimation of platelet aspirin resistance:detection by TEG platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol.2005; 46:1705-1709.
5 Barragan P. et al. (2003) Cathet Cardiovasc Intervent 59:295-302.
6 Gurbel P.A. et al. (2003) Circulation 107:2908-2913.
7 Muller I. et al. (2003) Thromb Haemost 89:783-787.
8 Schwarz U.R. et al. (1999) Thromb Haemost 82:1145-1152.
9 Gurbel PA, Bliden KP, Hayes KM, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005;45:1392-6
10 von Beckerath N, Kastrati A, Wieczorek A, et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J 2007;8:1814-9
11 Gurbel PA, Tantry US. Drug insight:clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 2006;3:387-95
12 Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2004;110:e340-437
13 Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109:3171-5
14 Samara WM, Bliden KP, Tantry US, et al. The difference between clopidogrel responsiveness and posttreatment platelet reactivity. Thromb Res 2005;115:89-94
15 Lev El, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention:the role of dual drug resistance. J Am Coll Cardiol 2006;47:27-33
16 Buonamici P, Marcucci R, Miglironi A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312-7
17 Frere C, Cuisset T, Quilici J, et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemost 2007;98:838-43
18 Cuisset T, Hamilos M, Sarma J, et al. Relation of low response to clopidogrel assessed with point-of-care assay to periprocedural myonecrosis in patients undergoing elective coronary stenting for stable angina pectoris. Am J Cardiol 2008; 101:1700-3
19 Gurbel PA, Bliden KP, Tantry US. Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting:results from the CLEAR PLATELETS lb study. J Am Coll Cardiol 2006;48:2186-91
20 Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting:results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005;46:1820-6
21 Gurbel PA, Antonino MJ, Bliden KP, et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention:a potential antiplatelet therapeutic target. Platelets 2008; 19:595-604
22 van der Meijden PE, Feijge MA, Giesen PL, et al. Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk. Thromb Haemost 2005;93:1128-36
23 Judge HM, Buckland RJ, Sugidachi A, et al. The active metabolite of prasugrel effectively blocks the platelet P2Y(12) receptor and inhibits procoagulant and pro-inflammatory platelet responses. Platelets 2008;19:125-33
24 Gurbel PA, Antonino MJ, Bliden KP, et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention:a potential antiplatelet therapeutic target. Platelets 2008; 19:595-604
25 Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thiomb Haemost 2006;4:542-9
26 Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance:a multicenter randomized prospective study. J Am Coll Cardiol 2008;51:1404-11
27 Bonello L, Paganelli F, Arpin-Bornet M, et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007;5:1630-6
28 Gurbel PA,Bliden KP,Zaman KA,et al. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets:results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005; 111:1153-1159
29 Gurbel PA,Bliden KP,Hayes KM,et al.The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45:1392-1396
30 Schroeder,W.S.,Ghobrial,L. Gandhi,P.J. Possible mechanisms of drug-induced aspirin and clopidogrel resistance. J. Thromb. Thrombolysis.2006; 22:139-150.
31 Wallentin L,Varenhorst C,James S,et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29:21-30
32 Pereillo JM, Maftouh M, Andrieu A, et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 2002;30:1288-95
33 Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-62
34 KA Kim,PW Park,SJ Hong et al. The Effect of CYP2C19 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Clopidogrel:A Possible Mechanism for Clopidogrel Resistance. Clinical pharmacology & Therapeutics.2008; 84(2):236-242.
35 Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108:2244-7
36 Fontana P, Hulot JS, De Moerloose P, Gaussem P. Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. J Thromb Haemost 2007;10:2153-5
37 Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-62
38 Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108:2244-7
39 Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10+12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics 2007; 12:1057-64
40 Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004; 109:166-71
41 Suh JW, Koo BK, Zhang SY, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ 2006; 12:1715-22
42 Neubauer H, Mugge A. Thienopyridines and statins:assessing a potential drug-drug interaction. Curr Pharm Des 2006; 12:1271-80
43 Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007;12:2429-36
44 Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008;51:1925-34
45 Gladding P, Webster M, Zeng I, et al. The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel. The PRINC (Plavix Response in Coronary Intervention) trial. J Am Coll Cardiol Interv 2008; 1:612-9
46 Simon T,Verstuyft C,Mary-Krause M,et al.; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360:363-375
47 Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood.2006;108(7):2244-2247.
48 Savi P, Pereillo J, Uzabiaga M, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000;84:891-96
49 叶颖.他汀类药物和氯吡格雷的相互作用.中国药房,2007,18(14)：1113
50 Pascal M, Herbert JM, Maffrand J P,et al 1 Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metabolism and Disposition,2002,30:1 288
51 Savi P, Zachayus JL, Delesque-Touchard N, et al. The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci 2006; 103:11069-74
52 Patrono C, Baigent C, Hirsh J, Roth G. American College of Chest Physicians. Antiplatelet drugs:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.8th edition. Chest 2008;133:199S-233S
53 Aleil B, Ravanat C, Cazenave JP, et al. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 2005;3:85-92
54 Gurbel PA, Tantry US. Drug insight:clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med.2006;3:387-95
55 Gurbel PA, Antonino MJ, Tantry US. Antiplatelet treatment of cardiovascular disease:a translational research perspective. Pol Arch Med Wewn 2008;118:289-97
56 Bal Dit Sollier C, Berge N, Boval B, et al. Functional variability of platelet response to clopidogrel correlates with P2Y(12) receptor occupancy. Thromb Haemost 2009;101:116-22
57 Ernest CS 2nd, Small DS, Rohatagi S, et al. Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease. J Pharmacokinet Pharmacodyn 2008;35:593-618
58 Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008;29:21-30
59 von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-,600-, and 900-mg loading doses of clopidogrel:results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen:Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005; 112:2946-50
60 季宏建,周小华,邹建军等.L C-MS/MS法测定人血浆中氯吡格雷的浓度及其药动学研究.中国药房,2009,120：584-586
61 Ramakrishna VSN,Vishwot tam N K,Manoj S,et al. Quantification of clopidogrel in human plasma by sensitive liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry,2006,20 (20):1695
62 Eisenstein EL,Anstrom KJ,Kong DF et al. Clopidogrel use and long term clinical outcomes after drug-eluting stent implantation. JAMA 2007; 297:159-168.
63 Gurbel PA,Tantry US. Drug insight:clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med.2006; 3:387-395
64 Hankey GJ,Eikelboom JW. Aspirin resistance. Lancet 2006; 367:606-17.
65 George Krasopoulos,Stephanie J Brister,W Scott Beattie et al. Aspirin "resistance" and risk of cardiovascular morbidity:systematic review and meta-analysis. BMJ published online 17 Jan 2008; doi:10.1136/bmj.39430.529549.BE
66 Cesari F,Marcucci R,Caporale R et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost.2008 May; 99(5):930-5.
67 Guthikonda S,Lev EI,Patel R et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin.J Thromb Haemost.2007 Mar; 5(3):490-6.
68 Perneby C,Wallen NH,Rooney C et al. Dose-and time-dependent antiplatelet effects of aspirin. Thromb Haemost.2006 Apr; 95(4):652-8.
69 Patrono C,Garcia Rodriguez LA,Landolfi R et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353:2373-83. Buchanan MR. Biological basis and clinical implications of acetylsalicylic acid resistance. Can J Cardiol 2006; 22:149-51.
70 Cohen HW,Crandall JP,Hailpern SM et al. Aspirin resistance associated with HbAlc and obesity in diabetic patients.J Diabetes Complications.2008 May-Jun; 22(3):224-8.
71 DiChiara J,Bliden KP,Tantry US et al. The effect of aspirin dosing on platelet function in diabetic and nondiabeticpatients:an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes.2007 Dec; 56(12):3014-9.
72 Gurbel PA,Bliden KP,DiChiara J et al. Evaluation of dose-related effects of aspirin on platelet function:results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation.2007 Jun 26; 115(25):3156-64.
73 Heistein LC,Scott WA,Zellers TM et al. Aspirin resistance in children with heart disease at risk for thromboembolism:prevalence and possible mechanisms. Pediatr Cardiol. 2008 Mar; 29(2):285-91.
74 Rozalski M,Boncler M,Luzak B et al. Genetic factors underlying differential blood platelet sensitivity to inhibitors. Pharmacol Rep 2005; 57:1-13.
75 Maree AO,Curtin RJ,Chubb A et al. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost 2005; 3:2340-5.
76 Gonzalez-Conejero R,Rivera J,Corral J et al. Biological assessment of aspirin efficacy on healthy individuals:heterogeneous response or aspirin failure? Stroke 2005; 36:276-80.
77 Hiibl W,Assadian A,Lax J et al. Assessing aspirin-induced attenuation of platelet reactivity by flow cytometry. Thromb Res.2007; 121 (1):135-43.
78 Ohmori T,Yatomi Y,Nonaka T et al. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity:involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. J Thromb Haemost.2006 Jun; 4(6):1271-8.
79 Lepantalo A,Mikkelsson J,Resendiz JC et al. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost 2006; 95:253-9.
80 Papafili A,Hill MR,Brull DJ et al. Common promoter variant in cyclooxygenase-2 represses gene expression:evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 2002; 22:1631-6.
81 Lev EI,Patel RT,Guthikonda S et al. Genetic polymorphisms of the platelet receptors P2Y(12),P2Y(1) and GP Ⅲa and response to aspirin and clopidogrel. Thromb Res 2007; 119 (3):355-60.
82 Giusti B,Gori AM,Marcucci R et al. Role of glycoprotein la gene polymorphisms in determining platelet function in myocardial infarction patients undergoing percutaneous coronary intervention on dual antiplatelet treatment. Atherosclerosis.2008 Jan; 196(1):341-8.
83 Lepantalo A,Mikkelsson J,Resendiz JC et al. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost 2006; 95:253-9.
84 Diener HC,Bogousslavsky J,Brass LM et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH):randomised,double-blind,placebo-controlled trial. Lancet 2004; 364:331-7.
85 Eikelboom JW,Hankey GJ,Thom J et al. Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin:a randomized crossover trial. J Thromb Haemost 2005; 3:2649-55.
86 Hetherington SL,Singh RK,Lodwick D et al. Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol 2005; 25:252-7。
87 Cuisset T,Frere C,Quilici J et al. Role of the T744C polymorphism of the P2Y12 gene on platelet response to a 600-mg loading dose of clopidogrel in 597 patients with non-ST-segment elevation acute coronary syndrome. Thromb Res.2007; 120(6):893-9.
88 Jefferson BK,Foster JH,McCarthy JJ et al. Aspirin resistance and a single gene. Am J Cardiol 2005; 95:805-8.
89 Schirmer M,Toliat MR,Haberl M et al. Genetic signature consistent with selection against the CYP3A4*1B allele in non-African populations. Pharmacogenet Genomics. 2006; 16:59-71.
90 Angiolillo DJ,Fernandez-Ortiz A,Bernardo E et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol.2006; 26; 1895-1900.
91 Jung-Won Suh,Bon-Kwon Koo,Shu-Ying Zhang et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel.CMAJ.2006 June; 174(12):1715-22
92 Hulot JS,BuraA,Villard E et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108:2244-7.
93 Kim KA,Park PW,Hong SJ et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel:a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther.2008 Aug; 84(2):236-42.
94 Simon T, Verstuyft C, Mary-Krause M, et al.; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-75
95 Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction:a cohort study. Lancet 2009;373:309-17
96 Simon T, Verstuyft C, Mary-Krause M, et al.; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-75
2 Caplain H, Donat F, Gaud C,et al. Pharmacokinetics of clopidogrel. S eminars in Thrombosis and Hemostasis,1999,25 (2):251
3 Gurbel PA, Becker RC, Mann KG, et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007,50:1822-1834.
4 Tantry US, Bliden KP,Gurbel PA. Overestimation of platelet aspirin resistance:detection by TEG platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol.2005; 46:1705-1709.
5 Barragan P. et al. (2003) Cathet Cardiovasc Intervent 59:295-302.
6 Gurbel P.A. et al. (2003) Circulation 107:2908-2913.
7 Muller I. et al. (2003) Thromb Haemost 89:783-787.
8 Schwarz U.R. et al. (1999) Thromb Haemost 82:1145-1152.
9 Gurbel PA, Bliden KP, Hayes KM, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005;45:1392-6
10 von Beckerath N, Kastrati A, Wieczorek A, et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J 2007;8:1814-9
11 Gurbel PA, Tantry US. Drug insight:clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 2006;3:387-95
12 Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2004;110:e340-437
13 Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109:3171-5
14 Samara WM, Bliden KP, Tantry US, et al. The difference between clopidogrel responsiveness and posttreatment platelet reactivity. Thromb Res 2005;115:89-94
15 Lev El, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention:the role of dual drug resistance. J Am Coll Cardiol 2006;47:27-33
16 Buonamici P, Marcucci R, Miglironi A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312-7
17 Frere C, Cuisset T, Quilici J, et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemost 2007;98:838-43
18 Cuisset T, Hamilos M, Sarma J, et al. Relation of low response to clopidogrel assessed with point-of-care assay to periprocedural myonecrosis in patients undergoing elective coronary stenting for stable angina pectoris. Am J Cardiol 2008; 101:1700-3
19 Gurbel PA, Bliden KP, Tantry US. Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting:results from the CLEAR PLATELETS lb study. J Am Coll Cardiol 2006;48:2186-91
20 Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting:results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005;46:1820-6
21 Gurbel PA, Antonino MJ, Bliden KP, et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention:a potential antiplatelet therapeutic target. Platelets 2008; 19:595-604
22 van der Meijden PE, Feijge MA, Giesen PL, et al. Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk. Thromb Haemost 2005;93:1128-36
23 Judge HM, Buckland RJ, Sugidachi A, et al. The active metabolite of prasugrel effectively blocks the platelet P2Y(12) receptor and inhibits procoagulant and pro-inflammatory platelet responses. Platelets 2008;19:125-33
24 Gurbel PA, Antonino MJ, Bliden KP, et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention:a potential antiplatelet therapeutic target. Platelets 2008; 19:595-604
25 Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thiomb Haemost 2006;4:542-9
26 Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance:a multicenter randomized prospective study. J Am Coll Cardiol 2008;51:1404-11
27 Bonello L, Paganelli F, Arpin-Bornet M, et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007;5:1630-6
28 Gurbel PA,Bliden KP,Zaman KA,et al. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets:results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005; 111:1153-1159
29 Gurbel PA,Bliden KP,Hayes KM,et al.The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45:1392-1396
30 Schroeder,W.S.,Ghobrial,L. Gandhi,P.J. Possible mechanisms of drug-induced aspirin and clopidogrel resistance. J. Thromb. Thrombolysis.2006; 22:139-150.
31 Wallentin L,Varenhorst C,James S,et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29:21-30
32 Pereillo JM, Maftouh M, Andrieu A, et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 2002;30:1288-95
33 Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-62
34 KA Kim,PW Park,SJ Hong et al. The Effect of CYP2C19 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Clopidogrel:A Possible Mechanism for Clopidogrel Resistance. Clinical pharmacology & Therapeutics.2008; 84(2):236-242.
35 Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108:2244-7
36 Fontana P, Hulot JS, De Moerloose P, Gaussem P. Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. J Thromb Haemost 2007;10:2153-5
37 Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-62
38 Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108:2244-7
39 Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10+12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics 2007; 12:1057-64
40 Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004; 109:166-71
41 Suh JW, Koo BK, Zhang SY, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ 2006; 12:1715-22
42 Neubauer H, Mugge A. Thienopyridines and statins:assessing a potential drug-drug interaction. Curr Pharm Des 2006; 12:1271-80
43 Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007;12:2429-36
44 Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008;51:1925-34
45 Gladding P, Webster M, Zeng I, et al. The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel. The PRINC (Plavix Response in Coronary Intervention) trial. J Am Coll Cardiol Interv 2008; 1:612-9
46 Simon T,Verstuyft C,Mary-Krause M,et al.; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360:363-375
47 Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood.2006;108(7):2244-2247.
48 Savi P, Pereillo J, Uzabiaga M, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000;84:891-96
49 叶颖.他汀类药物和氯吡格雷的相互作用.中国药房,2007,18(14)：1113
50 Pascal M, Herbert JM, Maffrand J P,et al 1 Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metabolism and Disposition,2002,30:1 288
51 Savi P, Zachayus JL, Delesque-Touchard N, et al. The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci 2006; 103:11069-74
52 Patrono C, Baigent C, Hirsh J, Roth G. American College of Chest Physicians. Antiplatelet drugs:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.8th edition. Chest 2008;133:199S-233S
53 Aleil B, Ravanat C, Cazenave JP, et al. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 2005;3:85-92
54 Gurbel PA, Tantry US. Drug insight:clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med.2006;3:387-95
55 Gurbel PA, Antonino MJ, Tantry US. Antiplatelet treatment of cardiovascular disease:a translational research perspective. Pol Arch Med Wewn 2008;118:289-97
56 Bal Dit Sollier C, Berge N, Boval B, et al. Functional variability of platelet response to clopidogrel correlates with P2Y(12) receptor occupancy. Thromb Haemost 2009;101:116-22
57 Ernest CS 2nd, Small DS, Rohatagi S, et al. Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease. J Pharmacokinet Pharmacodyn 2008;35:593-618
58 Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008;29:21-30
59 von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-,600-, and 900-mg loading doses of clopidogrel:results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen:Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005; 112:2946-50
60 季宏建,周小华,邹建军等.L C-MS/MS法测定人血浆中氯吡格雷的浓度及其药动学研究.中国药房,2009,120：584-586
61 Ramakrishna VSN,Vishwot tam N K,Manoj S,et al. Quantification of clopidogrel in human plasma by sensitive liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry,2006,20 (20):1695
62 Eisenstein EL,Anstrom KJ,Kong DF et al. Clopidogrel use and long term clinical outcomes after drug-eluting stent implantation. JAMA 2007; 297:159-168.
63 Gurbel PA,Tantry US. Drug insight:clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med.2006; 3:387-395
64 Hankey GJ,Eikelboom JW. Aspirin resistance. Lancet 2006; 367:606-17.
65 George Krasopoulos,Stephanie J Brister,W Scott Beattie et al. Aspirin "resistance" and risk of cardiovascular morbidity:systematic review and meta-analysis. BMJ published online 17 Jan 2008; doi:10.1136/bmj.39430.529549.BE
66 Cesari F,Marcucci R,Caporale R et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost.2008 May; 99(5):930-5.
67 Guthikonda S,Lev EI,Patel R et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin.J Thromb Haemost.2007 Mar; 5(3):490-6.
68 Perneby C,Wallen NH,Rooney C et al. Dose-and time-dependent antiplatelet effects of aspirin. Thromb Haemost.2006 Apr; 95(4):652-8.
69 Patrono C,Garcia Rodriguez LA,Landolfi R et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353:2373-83. Buchanan MR. Biological basis and clinical implications of acetylsalicylic acid resistance. Can J Cardiol 2006; 22:149-51.
70 Cohen HW,Crandall JP,Hailpern SM et al. Aspirin resistance associated with HbAlc and obesity in diabetic patients.J Diabetes Complications.2008 May-Jun; 22(3):224-8.
71 DiChiara J,Bliden KP,Tantry US et al. The effect of aspirin dosing on platelet function in diabetic and nondiabeticpatients:an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes.2007 Dec; 56(12):3014-9.
72 Gurbel PA,Bliden KP,DiChiara J et al. Evaluation of dose-related effects of aspirin on platelet function:results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation.2007 Jun 26; 115(25):3156-64.
73 Heistein LC,Scott WA,Zellers TM et al. Aspirin resistance in children with heart disease at risk for thromboembolism:prevalence and possible mechanisms. Pediatr Cardiol. 2008 Mar; 29(2):285-91.
74 Rozalski M,Boncler M,Luzak B et al. Genetic factors underlying differential blood platelet sensitivity to inhibitors. Pharmacol Rep 2005; 57:1-13.
75 Maree AO,Curtin RJ,Chubb A et al. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost 2005; 3:2340-5.
76 Gonzalez-Conejero R,Rivera J,Corral J et al. Biological assessment of aspirin efficacy on healthy individuals:heterogeneous response or aspirin failure? Stroke 2005; 36:276-80.
77 Hiibl W,Assadian A,Lax J et al. Assessing aspirin-induced attenuation of platelet reactivity by flow cytometry. Thromb Res.2007; 121 (1):135-43.
78 Ohmori T,Yatomi Y,Nonaka T et al. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity:involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. J Thromb Haemost.2006 Jun; 4(6):1271-8.
79 Lepantalo A,Mikkelsson J,Resendiz JC et al. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost 2006; 95:253-9.
80 Papafili A,Hill MR,Brull DJ et al. Common promoter variant in cyclooxygenase-2 represses gene expression:evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 2002; 22:1631-6.
81 Lev EI,Patel RT,Guthikonda S et al. Genetic polymorphisms of the platelet receptors P2Y(12),P2Y(1) and GP Ⅲa and response to aspirin and clopidogrel. Thromb Res 2007; 119 (3):355-60.
82 Giusti B,Gori AM,Marcucci R et al. Role of glycoprotein la gene polymorphisms in determining platelet function in myocardial infarction patients undergoing percutaneous coronary intervention on dual antiplatelet treatment. Atherosclerosis.2008 Jan; 196(1):341-8.
83 Lepantalo A,Mikkelsson J,Resendiz JC et al. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost 2006; 95:253-9.
84 Diener HC,Bogousslavsky J,Brass LM et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH):randomised,double-blind,placebo-controlled trial. Lancet 2004; 364:331-7.
85 Eikelboom JW,Hankey GJ,Thom J et al. Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin:a randomized crossover trial. J Thromb Haemost 2005; 3:2649-55.
86 Hetherington SL,Singh RK,Lodwick D et al. Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol 2005; 25:252-7。
87 Cuisset T,Frere C,Quilici J et al. Role of the T744C polymorphism of the P2Y12 gene on platelet response to a 600-mg loading dose of clopidogrel in 597 patients with non-ST-segment elevation acute coronary syndrome. Thromb Res.2007; 120(6):893-9.
88 Jefferson BK,Foster JH,McCarthy JJ et al. Aspirin resistance and a single gene. Am J Cardiol 2005; 95:805-8.
89 Schirmer M,Toliat MR,Haberl M et al. Genetic signature consistent with selection against the CYP3A4*1B allele in non-African populations. Pharmacogenet Genomics. 2006; 16:59-71.
90 Angiolillo DJ,Fernandez-Ortiz A,Bernardo E et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol.2006; 26; 1895-1900.
91 Jung-Won Suh,Bon-Kwon Koo,Shu-Ying Zhang et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel.CMAJ.2006 June; 174(12):1715-22
92 Hulot JS,BuraA,Villard E et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108:2244-7.
93 Kim KA,Park PW,Hong SJ et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel:a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther.2008 Aug; 84(2):236-42.
94 Simon T, Verstuyft C, Mary-Krause M, et al.; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-75
95 Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction:a cohort study. Lancet 2009;373:309-17
96 Simon T, Verstuyft C, Mary-Krause M, et al.; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-75