老年患者阿司匹林抵抗现患率调查与遗传易感性研究
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摘要
背景：动脉血栓性疾病已经成为我国首位死亡原因,阿司匹林在治疗与预防动脉血栓性疾病有着不可替代的地位,是抗动脉血栓治疗的基石。2009年,国际抗栓临床试验协作组(Antithrombotic Trialists'Collaboration),再次强调了阿司匹林在缺血性动脉疾病二级预防中的作用,Meta分析表明抗血小板治疗使联合终点事件下降1/4,非致命性心肌梗死减少1/3,非致命性中风减少1/4,血管疾病病死率减少1/6。然而,部分人群存在对阿司匹林治疗反应低下的现象,称为阿司匹林抵抗(aspirin resistance, AR).患者规律服用常规剂量的阿司匹林仍不能减少临床缺血性动脉血栓事件的发生,称为临床阿司匹林抵抗。通过实验室方法监测血小板聚集功能未得到有效抑制,称为生化阿司匹林抵抗或实验室阿司匹林抵抗。前瞻性临床研究的资料分析显示,实验室阿司匹林抵抗患者血管事件风险增加。实验室阿司匹林抵抗客观反应了血小板功能,可以作为阿司匹林抵抗与否的区分标准。
阿司匹林抵抗发病机制仍未完全清楚。通过对老年人群阿司匹林抵抗的现患率调查及阿司匹林抵抗发生的基因学基础进行研究,揭示阿司匹林抵抗发生机制是我们研究的主要目的。
第一部分老年患者阿司匹林抵抗现患率调查
研究目的：
调查AR现患率,评价光比浊法和血栓弹力图法诊断AR的一致性和科学性。
研究对象：2008年4月～2010年7月解放军总医院、解放军309医院、海军总医院以及25个干休所,具有冠心病、脑梗死、外周动脉硬化性疾病的汉族人群,服用阿司匹林75mg～100mg,≥1个月。患者年龄≥65岁。排除标准：服用氯吡格雷,噻氯匹定,潘生丁或其他非甾体抗炎药,肝素或低分子量肝素。急性血管事件患者；血小板计数<150.000/μL或>450.000/μL,血红蛋白<8g/L。不能配合调查,不愿参加调查者。
研究方法:
采用病例-对照研究方法。内容包括问卷调查、临床检验、血栓弹力图、光比浊法血小板聚集试验；血小板抗原PAC-1、CD62P等项目。
AR诊断标准：Ⅰ.AA(花生四烯酸)作诱导剂,血小板聚集率≥20%。Ⅱ.ADP(二磷酸腺苷)作诱导剂,血小板聚集率≥70%。符合2项为阿司匹林抵抗(AR)；符合其中一项为阿司匹林半抵抗(semi-AR);两项均不符合者为阿司匹林敏感(aspirin sensitivity).Ⅲ. AA作诱导剂,血栓弹力图法检测血小板抑制率≤50%。
结果分析使用统计软件SPSS13.0.
研究结果：
服用阿司匹林患者临床特征：共计调查了431例冠心病、缺血性脑血管疾病、缺血性外周动脉硬化性疾病的汉族患者。男283例,女148例,年龄：65岁～92岁,平均年龄73.824±8.03岁。
不同方法检测阿司匹林抵抗发生率
AA诱导光比浊法(LTAAA):AR检出率13.69%。ADP诱导光比浊法(LTAADP):AR检出率30.16%。AA诱导血栓弹力图(TEGAA):AR检出率23.67%。三种方法一致性差,kappa均<0.4。LTAAA联合LTAADP法：AR检出率8.35%；semi-AR检出率38.05%。我们在研究中发现：假如采用LTAAA联合TEGAA法：AR：8.82%,semi-AR:19.72%。剔除semi-AR后,与传统应用LTAAA联合LTAADP法诊断AR相比,在诊断AR二者具有很好的一致性,kappa=0.981。
结论：
AR患病率直接与血小板功能检查方法相关,两种方法联合,能够提高AR诊断的可靠性和一致性。在老年人群中,采用LTAAA法AR现患率13.69%。采用LTAAA联合LTAADP法,AR现患率8.35%。采用LTAAA联合TEGAA法,AR现患率为8.82%。
第二部分SNP与阿司匹林抵抗遗传关联性分析
研究目的：
》筛查与阿司匹林抵抗关联的基因多态性位点(SNP),揭示阿司匹林抵抗发病的基因学基础。
研究方法：
》采用病例-对照研究方法基于LATAA分类法：AR=59例(病例)与AS=372例(对照)。基于LATAA联合LATADP分类法：AR=36例,semi-AR=164例,AS=231例。两两之间比较SNPs差异。
>采用候选基因法：入选14个基因27SNPs位点。
>结果分析应用haploview4.2软件、THESIS软件和在线软件SNPstats等。
研究结果：
1. HO-1rs2071746(-413A>T)与AR关联
与野生型A-等位基因相比,T-等位基因为AR发生的危险因素；T等位基因的最优遗传模式是显性遗传模式；在显性遗传模式下,与野生型AA相比,AT+TT基因型显著增加AR风险；经年龄、性别校正后,非条件Logistic回归分析发现,AT+TT基因型同样显著增加AR发病风险。
2.COX-1基因多态性与AR关联
COX-1rs1330344(-1676A>G),与野生型A等位基因相比,G等位基因增加AR风险；G等位基因最优遗传模式为隐性遗传；基因型差异无显著性；以rs1330344为主的单体型与AR相关联,突变型是AR发生的危险因素。以rs1330344为主构成的单体型与AR相关联。
3.ACE基因rs4332(547C/T)与semi-AR相关
野生型C等位基因是semi-AR危险因素,突变基因T对semi-AR有保护作用；突变基因T的最优遗传模式为显性遗传模式；在显性遗传模式下,与野生型CC相比,CT+TT基因型与AR负相关；经年龄、性别校正后,非条件Logistic回归分析发现,CT+TT基因型显著降低AR发病风险。
结论：
》COX-1基因多态性与中国汉族人群AR相关联；COX-1rs1330344(-1676A>G)多态性是影响汉族人AR发病的主要SNP位点,以COX-1rs1330344为主的单体型与AR发病相关联。
(?)HO-1rs2071746(-413A>T)与中国汉族人群AR相关联。
(?)ACErs4332(547C/T)与中国汉族人群semi-AR关联。
Background:Atherothrombotic diseases have become the first cause of death in old Chinese people. Aspirin is a cornerstone of treatment and prevention of ischeraic atherothrombotic diseases. In2009, Antithrombotic Trialists'(ATT) Collaboration re-emphasized a secondary prevention of cardiovascular and cerebrovascular disease of aspirin. Meta analysis showed that antiplatelet therapy can decrease1/4combined endpoint,1/3non-fatal myocardial infarction,1/4non-fatal stroke and decrease1/6vascular mortality. However, some people poorly response to aspirin application. The phenomenon is defined as aspirin resistant (AR). Patients taking regular doses of aspirin cannot reduce ischemic events, known as clinical aspirin resistance. Monitored by laboratory methods, platelet aggregation cannot be effectively inhibited after taking aspirin, known as the laboratory or biochemical aspirin resistance. Prospective analysis from clinical studies has shown that patients with laboratory aspirin resistance have an increased risk of adverse clinical outcomes. Although definition of AR by platelet function isn't standardized, it is still necessary to aspirin administration.
The mechanism of aspirin resistance remains unclear. This study aimed to investigate the mechanism of genetic susceptibility to AR and prevalence of aspirin resistance in old patients.
Part1. Prevalence of Aspirin Resistance in Old Patients
Aims:Light transmittance aggregation and thromboelastography are routine platelet function tests in diagnosis of AR in our hospital. This study sought to determine the prevalence of aspirin resistance using those two methods.
Methods:
Patients:For this study, information and DNA samples were obtained from consecutive patients in Chinese Han population who were present between April 2008and June2010in Beijing with CAD, stroke and PAD. Those patients had been receiving regular aspirin therapy (75-100mg daily) for at least4weeks. Inclusion criteria were age≥65years. Exclusion criteria included:the use of Clopidogrel, Ticlopidine, Dipyridamole or other nonsteroidal anti-inflammatory drugs, heparin or low molecular weight heparin; acute vascular events; platelet count<150000000/L or>450000000/L; haemoglobin<8g/dL. All patients provided written informed consent and questionnaire before inclusion in the study.
Blood Sample: Blood samples were obtained from patients for measurement of blood routine and CD62P (P-selectin) and PAC-1(activated GPⅡb/Ⅲa receptors), hs-CRP, type-B natriuretic peptide (BNP), HCY, antithrombin Ⅲ(ATⅢ) and other biochemistry measurements.
Definition of aspirin resistance:On the basis of light transmitted aggregation (LTA) assay, the definition of AR was aggregation of≥70%with ADP, and of≥20%with AA. Aspirin-sensitivity was indicated by neither of these criteria being met; complete AR by both criteria being met; only one of the two criteria met was deemed semi-AR. The definition of AR by thromboelastogram is≥50%via AA-induced whole blood aggregation.
Results:The prevalence of aspirin resistance varied according to the assay used:13.69%-30.16%.
Conclusion:Poor correlations and agreement among AA-induced light transmitted aggregation, ADP-induced light transmitted aggregation and AA-induced whole blood aggregation by thromboelastogram defined as aspirin resistance. However, in diagnosis of complete AR, the method of AA-induced aggregation combined with AA-induced TEG is consistent with the method of AA-induced aggregation combined with ADP-induced aggregation.
Part2. Aspirin Resistance and Single-nucleotide Polymorphisms
Aims:To detect the genetic susceptibility of AR.
Methods:The correlation of AR with27single nucleotide polymorphisms (SNPs) in14candidate genes was investigated. By AA-induced LTA method,59participants are served for cases,372participants for controls. By LTAAA combined with TEGAA,36participants are served for AR,164participants for semi-AR, and231participants for aspirin sensitivity. These groups are comparable.
Results:In this case-control study, HO-1rs2071746(-413A> T) significantly associated with AR or complete AR, wild type A-allele and AA-genotype is a protective factor for AR. COX1rs1330344(-1676A>G) and COX1haplotype were also significantly associated with AR. G-allele and GG-genotype are risk factors for AR. Mutant of COX1haplotype is also a risk factor to AR. ACE rs4332(14848C/T) is only associated with semi-AR, wild-type C allele and CC genotypes are risk factors for semi-AR. The remaining SNPs and haplotypes are not associated with AR and semi-AR.
Conclusions:Our results indicate that AR is associated with HO-1rs2071746gene polymorphism, COX1rs1330344(-1676A>G) and COX1haplotype in Chinese Han population. ACE rs4332(547C/T) is only associated with semi-AR, the mutant T allele is a protective factor for semi-AR. The genetic susceptibility of AR between semi-AR is different.
阿司匹林抵抗发病机制仍未完全清楚。通过对老年人群阿司匹林抵抗的现患率调查及阿司匹林抵抗发生的基因学基础进行研究,揭示阿司匹林抵抗发生机制是我们研究的主要目的。
第一部分老年患者阿司匹林抵抗现患率调查
研究目的：
调查AR现患率,评价光比浊法和血栓弹力图法诊断AR的一致性和科学性。
研究对象：2008年4月～2010年7月解放军总医院、解放军309医院、海军总医院以及25个干休所,具有冠心病、脑梗死、外周动脉硬化性疾病的汉族人群,服用阿司匹林75mg～100mg,≥1个月。患者年龄≥65岁。排除标准：服用氯吡格雷,噻氯匹定,潘生丁或其他非甾体抗炎药,肝素或低分子量肝素。急性血管事件患者；血小板计数<150.000/μL或>450.000/μL,血红蛋白<8g/L。不能配合调查,不愿参加调查者。
研究方法:
采用病例-对照研究方法。内容包括问卷调查、临床检验、血栓弹力图、光比浊法血小板聚集试验；血小板抗原PAC-1、CD62P等项目。
AR诊断标准：Ⅰ.AA(花生四烯酸)作诱导剂,血小板聚集率≥20%。Ⅱ.ADP(二磷酸腺苷)作诱导剂,血小板聚集率≥70%。符合2项为阿司匹林抵抗(AR)；符合其中一项为阿司匹林半抵抗(semi-AR);两项均不符合者为阿司匹林敏感(aspirin sensitivity).Ⅲ. AA作诱导剂,血栓弹力图法检测血小板抑制率≤50%。
结果分析使用统计软件SPSS13.0.
研究结果：
服用阿司匹林患者临床特征：共计调查了431例冠心病、缺血性脑血管疾病、缺血性外周动脉硬化性疾病的汉族患者。男283例,女148例,年龄：65岁～92岁,平均年龄73.824±8.03岁。
不同方法检测阿司匹林抵抗发生率
AA诱导光比浊法(LTAAA):AR检出率13.69%。ADP诱导光比浊法(LTAADP):AR检出率30.16%。AA诱导血栓弹力图(TEGAA):AR检出率23.67%。三种方法一致性差,kappa均<0.4。LTAAA联合LTAADP法：AR检出率8.35%；semi-AR检出率38.05%。我们在研究中发现：假如采用LTAAA联合TEGAA法：AR：8.82%,semi-AR:19.72%。剔除semi-AR后,与传统应用LTAAA联合LTAADP法诊断AR相比,在诊断AR二者具有很好的一致性,kappa=0.981。
结论：
AR患病率直接与血小板功能检查方法相关,两种方法联合,能够提高AR诊断的可靠性和一致性。在老年人群中,采用LTAAA法AR现患率13.69%。采用LTAAA联合LTAADP法,AR现患率8.35%。采用LTAAA联合TEGAA法,AR现患率为8.82%。
第二部分SNP与阿司匹林抵抗遗传关联性分析
研究目的：
》筛查与阿司匹林抵抗关联的基因多态性位点(SNP),揭示阿司匹林抵抗发病的基因学基础。
研究方法：
》采用病例-对照研究方法基于LATAA分类法：AR=59例(病例)与AS=372例(对照)。基于LATAA联合LATADP分类法：AR=36例,semi-AR=164例,AS=231例。两两之间比较SNPs差异。
>采用候选基因法：入选14个基因27SNPs位点。
>结果分析应用haploview4.2软件、THESIS软件和在线软件SNPstats等。
研究结果：
1. HO-1rs2071746(-413A>T)与AR关联
与野生型A-等位基因相比,T-等位基因为AR发生的危险因素；T等位基因的最优遗传模式是显性遗传模式；在显性遗传模式下,与野生型AA相比,AT+TT基因型显著增加AR风险；经年龄、性别校正后,非条件Logistic回归分析发现,AT+TT基因型同样显著增加AR发病风险。
2.COX-1基因多态性与AR关联
COX-1rs1330344(-1676A>G),与野生型A等位基因相比,G等位基因增加AR风险；G等位基因最优遗传模式为隐性遗传；基因型差异无显著性；以rs1330344为主的单体型与AR相关联,突变型是AR发生的危险因素。以rs1330344为主构成的单体型与AR相关联。
3.ACE基因rs4332(547C/T)与semi-AR相关
野生型C等位基因是semi-AR危险因素,突变基因T对semi-AR有保护作用；突变基因T的最优遗传模式为显性遗传模式；在显性遗传模式下,与野生型CC相比,CT+TT基因型与AR负相关；经年龄、性别校正后,非条件Logistic回归分析发现,CT+TT基因型显著降低AR发病风险。
结论：
》COX-1基因多态性与中国汉族人群AR相关联；COX-1rs1330344(-1676A>G)多态性是影响汉族人AR发病的主要SNP位点,以COX-1rs1330344为主的单体型与AR发病相关联。
(?)HO-1rs2071746(-413A>T)与中国汉族人群AR相关联。
(?)ACErs4332(547C/T)与中国汉族人群semi-AR关联。
Background:Atherothrombotic diseases have become the first cause of death in old Chinese people. Aspirin is a cornerstone of treatment and prevention of ischeraic atherothrombotic diseases. In2009, Antithrombotic Trialists'(ATT) Collaboration re-emphasized a secondary prevention of cardiovascular and cerebrovascular disease of aspirin. Meta analysis showed that antiplatelet therapy can decrease1/4combined endpoint,1/3non-fatal myocardial infarction,1/4non-fatal stroke and decrease1/6vascular mortality. However, some people poorly response to aspirin application. The phenomenon is defined as aspirin resistant (AR). Patients taking regular doses of aspirin cannot reduce ischemic events, known as clinical aspirin resistance. Monitored by laboratory methods, platelet aggregation cannot be effectively inhibited after taking aspirin, known as the laboratory or biochemical aspirin resistance. Prospective analysis from clinical studies has shown that patients with laboratory aspirin resistance have an increased risk of adverse clinical outcomes. Although definition of AR by platelet function isn't standardized, it is still necessary to aspirin administration.
The mechanism of aspirin resistance remains unclear. This study aimed to investigate the mechanism of genetic susceptibility to AR and prevalence of aspirin resistance in old patients.
Part1. Prevalence of Aspirin Resistance in Old Patients
Aims:Light transmittance aggregation and thromboelastography are routine platelet function tests in diagnosis of AR in our hospital. This study sought to determine the prevalence of aspirin resistance using those two methods.
Methods:
Patients:For this study, information and DNA samples were obtained from consecutive patients in Chinese Han population who were present between April 2008and June2010in Beijing with CAD, stroke and PAD. Those patients had been receiving regular aspirin therapy (75-100mg daily) for at least4weeks. Inclusion criteria were age≥65years. Exclusion criteria included:the use of Clopidogrel, Ticlopidine, Dipyridamole or other nonsteroidal anti-inflammatory drugs, heparin or low molecular weight heparin; acute vascular events; platelet count<150000000/L or>450000000/L; haemoglobin<8g/dL. All patients provided written informed consent and questionnaire before inclusion in the study.
Blood Sample: Blood samples were obtained from patients for measurement of blood routine and CD62P (P-selectin) and PAC-1(activated GPⅡb/Ⅲa receptors), hs-CRP, type-B natriuretic peptide (BNP), HCY, antithrombin Ⅲ(ATⅢ) and other biochemistry measurements.
Definition of aspirin resistance:On the basis of light transmitted aggregation (LTA) assay, the definition of AR was aggregation of≥70%with ADP, and of≥20%with AA. Aspirin-sensitivity was indicated by neither of these criteria being met; complete AR by both criteria being met; only one of the two criteria met was deemed semi-AR. The definition of AR by thromboelastogram is≥50%via AA-induced whole blood aggregation.
Results:The prevalence of aspirin resistance varied according to the assay used:13.69%-30.16%.
Conclusion:Poor correlations and agreement among AA-induced light transmitted aggregation, ADP-induced light transmitted aggregation and AA-induced whole blood aggregation by thromboelastogram defined as aspirin resistance. However, in diagnosis of complete AR, the method of AA-induced aggregation combined with AA-induced TEG is consistent with the method of AA-induced aggregation combined with ADP-induced aggregation.
Part2. Aspirin Resistance and Single-nucleotide Polymorphisms
Aims:To detect the genetic susceptibility of AR.
Methods:The correlation of AR with27single nucleotide polymorphisms (SNPs) in14candidate genes was investigated. By AA-induced LTA method,59participants are served for cases,372participants for controls. By LTAAA combined with TEGAA,36participants are served for AR,164participants for semi-AR, and231participants for aspirin sensitivity. These groups are comparable.
Results:In this case-control study, HO-1rs2071746(-413A> T) significantly associated with AR or complete AR, wild type A-allele and AA-genotype is a protective factor for AR. COX1rs1330344(-1676A>G) and COX1haplotype were also significantly associated with AR. G-allele and GG-genotype are risk factors for AR. Mutant of COX1haplotype is also a risk factor to AR. ACE rs4332(14848C/T) is only associated with semi-AR, wild-type C allele and CC genotypes are risk factors for semi-AR. The remaining SNPs and haplotypes are not associated with AR and semi-AR.
Conclusions:Our results indicate that AR is associated with HO-1rs2071746gene polymorphism, COX1rs1330344(-1676A>G) and COX1haplotype in Chinese Han population. ACE rs4332(547C/T) is only associated with semi-AR, the mutant T allele is a protective factor for semi-AR. The genetic susceptibility of AR between semi-AR is different.
引文
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12. Woo KS, Kim BR, Kim JE, et al. Determination of the prevalence of aspirin and clopidogrel resistances in patients with coronary artery disease by using various platelet-function tests. Korean J Lab Med.2010; 30(5):460-8.
13. Awtry EH, Loscalzo J. Aspirin. Circulation.2000; 101:1206-18.
14. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008; 359:938-49.
15. Braunwald E, Angiolillo D, Bates E, et al. Assessing the current role of platelet function testing. Clin Cardiol.2008; 31:110-16.
16. Pusch G, Feher G, Kotai K, et al. Aspirin resistance:focus on clinical endpoints J Cardiovasc Pharmacol.2008; 52:475-84.
17. Feher G, Pusch G, Szapary L. Optical aggregometry and aspirin resistance. Acta Neurol Scand.2009; 119:139.
18. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003;110(5-6):255-8.
19. McGeer PL, McGeer EG, Yasojima K. Expression of COX-1 and COX-2 mRNAs in atherosclerotic plaques. Exp Gerontol.2002; 37(7):925-9.
20. Karon BS, Wockenfus A, Scott R, et al. Aspirin responsiveness in healthy volunteers measured with multiple assay platforms. Clin Chem. 2008;54:1060-5.
21. Frelinger A, Furman MI, Linden MD, et al. Residual AA-induced platelet activation via an adenosine diphosphate-dependent but COX-1- and COX-2-independent pathway:a 700-patient study of aspirin resistance. Circulation.2006; 113(25):2888-96.
22. Gasparyan AY, Watson T, Lip GY. The Role of Aspirin in Cardiovascular Prevention Implications of Aspirin Resistance. J Am Coll Cardiol.2008; 51(19):1829-43.
23. Gum PA, Kottke-Marchant K, PA W, et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. Am Coll Cardiol.2003; 41(6):961-5.
24. Cohen HW, Crandall JP, Hailpern SM, et al. Aspirin resistance associated with HbA1c and obesity in diabetic patients. J Diabetes Complications. 2008; 22(3):224-8.
25. Sane DC, McKee SA, Malinin AI, et al. Frequency of aspirin resistance in patients with congestive heart failure treated with antecedent aspirin. Am J Cardiol 2002; 90(8):893-5.
26. Tanrikulu A M, Ozben B, Koc M. Aspirin resistance in patients with chronic renal failure. J Nephrol.2011 Jan 17[Epub ahead of print].
27. Ikeda T, Taniguchi R, Watanabe S, et al. Characterization of the antiplatelet effect of aspirin at enrollment and after 2-year follow-up in a real clinical setting in Japan. Circ J.2010 74(6):1227-35.
28. Kour D, Tandon V, R, Kapoor B, et al. Aspirin Resistance J Med Edu & Res.2006; 8(2):116-7.
29. Bauriedel G, Skowasch D, Schneider M, et al. Antiplatelet effects of angiotensin-converting enzyme inhibitors compared with aspirin and clopidogrel:A pilot study with whole-blood aggregometry Am Heart J. 2003; 145:343-8.
30. Reavey-Cantwell JF, Fox WC, Reichwage BD, et al. Factors associated with aspirin resistance in patients premedicated with aspirin and clopidogrel for endovascular neurosurgery. Neurosurgery.2009; 64((5):890-5.
31. Pignone M, Alberts MJ, Colwell J A, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes. J Am Coll Cardiol.2010; 55(25):2878-86.
32. Neubauer H, Kaiser AF, Endres HG, et a 1. Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance--the BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy. BMC Med.2011 12:9:3.
33. El-Atat F, Sarkar K, Kodali V, et al. A randomized pilot trial for aggressive therapeutic approaches in aspirin-resistant patients undergoing percutaneous coronary intervention. Invasive Cardiol.2011; 23(1):9-13.
34. Stef G, Csiszar A, Ziangmin Z, et al. Inhibition of NAD(P)H oxidase attenuates aggregation of platelets from high-risk cardiac patients with aspirin resistance. Pharmacol Rep.2007; 59:428-36.
35. Poston RS, Gu J, White C, et al. Perioperative management of aspirin resistance after off-pump coronary artery bypass grafting:possible role for aprotinin. Transfusion.2008; 48:39S-46S.
1. Musunuru K, Post WS, Herzog W, et al. Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity:a potential mechanism for increased vascular disease. Circ Cardiovasc Genet.2010; 3(5):445-53.
2. Agundez JA, Martinez, Perez-Sala D, et al. Pharmacogenomics in aspirin intolerance. Curr Drug Metab.2009; 10(9):998-1008.
3. 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.
4. Fujiwara T, Ikeda M, Esumi K, et al. Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity. Pharmacogenomics J.2007; 7(6):395-403
5. Maree AO, Curtin RJ. Chubb A. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. Thromb Haemost.2005; 3(10):2340-5.
6. Pettinella C, Romano M, Stuppia L. Cyclooxygenase-1 haplotype C50T/A-842G does not affect platelet response to aspirin. Thromb Haemost. 2009101(4):687-90.
7. Li Q, Chen BL, Ozdemir V. Frequency of genetic polymorphisms of COX1, GPⅢa and P2Y1 in a Chinese population and association with attenuated response to aspirin. Pharmacogenomics J.2007; 8(6).
8. Kunicki TJ, Williams SA, Nugent DJ, et al. Lack of association between aspirin responsiveness and seven candidate gene haplotypes in patients with symptomatic vascular disease. Thromb Haemost.2009; 101(1):123-33.
9. Motovska Z, Kvasnicka J, Hajkova J. Platelet gene polymorphisms and risk of bleeding in patients undergoing elective coronary angiography:a genetic substudy of the PRAGUE-8 trial. Atherosclerosis.2010; 212(2):548-52.
10. Shi J, Misso NL, Duffy DL. Cyclooxygenase-1 gene polymorphisms in patients with different asthma phenotypes and atopy. Eur Respir J.2005; 26(2):249-56.
11. F u rst R, Blumenthal SB, Kiemer AK, et al. Nuclear factor-kappa B-independent anti-inflammatory action of salicylate in human endothelial cells:induction of heme oxygenase-1 by the c-jun N-terminal kinase/activator protein-1 pathway. J Pharmacol Exp Ther.2006;318(1):389-94.
12. Grosser N, Abate A, Oberle S, et al. Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochem Biophys Res Commun.2003; 308:956-60.
13. Pae HO, Lee YC, Chung HT. Heme oxygenase-1 and carbon monoxide: emerging therapeutic targets in inflammation and allergy. Recent Pat Inflamm Allergy Drug Discov.2008; 2(3):159-65.
14. Stocker R, Perrella MA. Heme oxygenase-1:a novel drug target for atherosclerotic diseases?. Circulation.2006; 114(20):2178-89.
15. Lavrovsky Y, Schwartzman ML, Levere RD, et al. Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc Natl Acad Sci U S A.1994; 91(13):5987-91.
16. Alam J, Cook JL. How many transcription factors does it take to turn on the heme oxygenase-1 gene? Am J Respir Cell Mol Biol.2007; 36(2):166-74.
17. Exner M, Minar E, Wagner O, et al. The role of heme oxygenase-1 promoter polymorphisms in human disease. Free Radic Biol Med.2004;37(8):1097-104.
18. Levonen AL, Vahakangas E, Koponen JK, et al. Antioxidant gene therapy for cardiovascular disease:current status and future perspectives. Circulation. 2008; 117(16):2142-50.
19. Kim TH, Chang HS, Park SM, et al. Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmatics. Clin Exp Allergy.2008; 38(11):1727-37.
20. Hu J, Miyatake F, Aizu Y, et al. Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population. Neurosci Lett. 1999; 17(277).
21. Tazawa R, Xu XM, Wu KK, et al. Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene. Biochem Biophys Res Commun.1994; 203(1):190-9.
22. Kranzhofer R, J. R. Aspirin resistance in coronary artery disease is correlated to elevated markers for oxidative stress but not to the expression of cyclooxygenase (COX) 1/2, a novel COX-1 polymorphism or the P1A(1/2) polymorphism. Platelets.2006; 17(3):163-9.
23. Maguire J, Thakkinstian A, Levi C, et al. J Stroke Cerebrovasc Dis. Impact of COX-2 rs5275 and rs20417 and GPIIIa rs5918 polymorphisms on 90-day ischemic stroke functional outcome:a novel finding.2011; 20(2):134-44.
24. McGeer PL, McGeer EG, Yasojima K. Expression of COX-1 and COX-2 mRNAs in atherosclerotic plaques. Exp Gerontol.2002; 37(7):925-9.
25. Fontana P, Dupont A, Gandrille S. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation.2003; 108(8):989-95.
26. Zee RY, Michaud SE, Diehl KA, et al. Purinergic receptor P2Y, G-protein coupled,12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism. Atherosclerosis.2008; 197(2):694-9.
27. Goodman T, Ferro A, Sharma P. Pharmacogenetics of aspirin resistance:a comprehensive systematic review. Br J Clin Pharmacol.2008; 66(2):222-32.
28. Nacmias B, Tedde A, Bagnoli S, et al. Lack of implication for CALHM1 P86L common variation in Italian patients with early and late onset Alzheimer's disease. J Alzheimers Dis.2010; 20(1):37-41.
29. Lambert JC, Sleegers K, Gonzdlez-Perez A, et al. he CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease:a meta-analysis study. J Alzheimers Dis.2010;22(1):247-55.
30. Kharbanda RK,Walton B, Allen M, et al. Prevention of inflammation-induced endothelial dysfunction:a novel vasculo-protective action of aspirin. Circulation.2002; 105(22):2600-4.
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13. Gum PA, Kottke-Marchant K, Welsh PA et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease [J]. J Am Coll Cardiol.2003,41(6):961-5.
14. Cohen HW, Crandall JP, Hailpern SM et al. Aspirin resistance associated with HbAlc and obesity in diabetic patients [J]. J Diabetes Complications.2008, 22(3):224-8.
15. Sane DC, McKee SA, Malinin AI et al. Frequency of aspirin resistance in patients with congestive heart failure treated with antecedent aspirin [J]. Am J Cardiol. 2002 90(8):893-5.
16. D Kour, VR Tandon, B Kapoor et al. Aspirin Resistance [J]. J Med Edu & Res. 2006,8(2):116-117.
17. Bauriedel G, Skowasch D, Schneider M et al.Antiplatelet effects of angiotensin-converting enzyme inhibitors compared with aspirin and clopidogrel:A pilot study with whole-blood aggregometry [J]. Am Heart J.2003,145:343-348.
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24. Robert Y.L. Zee a, Sherri E. Michaud a, Kirsti A. Diehl a, Purinergic receptor P2Y, G-protein coupled,12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism [J]. Atherosclerosis,2008, 197:694-699.
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30. Maree AO, Curtin RJ, Chubb A et al.Cyclooxygenase-1 haplotype modulates platelet response to aspirin [J]. J Thromb Haemost.2005,3(10):2340-5.
31. Michelson AD.Aspirin resistance [J].Pathophysiol Haemost Thromb.2006, 35(1-2):5-9.
32. Violi F, Pignatelli P.Aspirin resistance:is this term meaningful [J]? Curr Opin Hematol.2006,13(5):331-6.
32. Violi F, Pignatelli P. The need for a consistent definition of "aspirin resistance" [J]. J Thromb Haemost.2006,4(7):1618-9.
34. Gasparyan AY. Aspirin and clopidogrel resistance:methodological challenges and opportunities [J].Vasc Health Risk Manag.2010,6:109-12.
35. Eikelboom JW, Hankey GJ. Aspirin resistance:a new independent predictor of vascular events [J]? J Am Coll Cardiol.2003,41(6):966-8.
2. Snoep JD, Hovens MM, Eikenboom JC, et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events:a systematic review and meta-analysis. Archives of internal medicine.2007; 167(15):1593-9.
3. Feher G, Feher A, Pusch G, et al. Clinical importance of aspirin and clopidogrel resistance. World J Cardiol.2010; 2(7):171-86.
4. Mehta JL, Mohandas B. Aspirin resistance:Fact or fiction? A point of view. World J Cardiol 2010; 2(9):280-8.
5. Kuliczkowski W, Witkowski A, Polonski L, et al. Interindividual variability in the response to oral antiplatelet drugs:a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J.2009; 30426-35.
6. Krasopoulos G, Brister SJ, Beattie WS, et al. Aspirin "resistance" and risk of cardiovascular morbidity:systematic review and meta-analysis.BMJ. 2008; 336(7637):195-8.
7. Lordkipanidze M, Pharand C, Schampaert E, et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J. 2007;28:1702-8.
8. 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; 115:3156-64.
9. Harrison P, Segal H, Silver L, et al. Lack of reproducibility of assessment of aspirin responsiveness by optical aggregometry and two platelet function tests. Platelets.2008; 19:119-24.
10. Chakroun T, Addad F, Abderazek F, et al. Screening for aspirin resistance in stable coronary artery patients by three different tests. Thromb Res. 2007; 121:413-418.
11. Renda G, Zurro M, Malatesta G. Inconsistency of different methods for assessing ex vivo platelet function:relevance for the detection of aspirin resistance.Haematologica.2010; 95(12):2095-101.
12. Woo KS, Kim BR, Kim JE, et al. Determination of the prevalence of aspirin and clopidogrel resistances in patients with coronary artery disease by using various platelet-function tests. Korean J Lab Med.2010; 30(5):460-8.
13. Awtry EH, Loscalzo J. Aspirin. Circulation.2000; 101:1206-18.
14. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008; 359:938-49.
15. Braunwald E, Angiolillo D, Bates E, et al. Assessing the current role of platelet function testing. Clin Cardiol.2008; 31:110-16.
16. Pusch G, Feher G, Kotai K, et al. Aspirin resistance:focus on clinical endpoints J Cardiovasc Pharmacol.2008; 52:475-84.
17. Feher G, Pusch G, Szapary L. Optical aggregometry and aspirin resistance. Acta Neurol Scand.2009; 119:139.
18. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003;110(5-6):255-8.
19. McGeer PL, McGeer EG, Yasojima K. Expression of COX-1 and COX-2 mRNAs in atherosclerotic plaques. Exp Gerontol.2002; 37(7):925-9.
20. Karon BS, Wockenfus A, Scott R, et al. Aspirin responsiveness in healthy volunteers measured with multiple assay platforms. Clin Chem. 2008;54:1060-5.
21. Frelinger A, Furman MI, Linden MD, et al. Residual AA-induced platelet activation via an adenosine diphosphate-dependent but COX-1- and COX-2-independent pathway:a 700-patient study of aspirin resistance. Circulation.2006; 113(25):2888-96.
22. Gasparyan AY, Watson T, Lip GY. The Role of Aspirin in Cardiovascular Prevention Implications of Aspirin Resistance. J Am Coll Cardiol.2008; 51(19):1829-43.
23. Gum PA, Kottke-Marchant K, PA W, et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. Am Coll Cardiol.2003; 41(6):961-5.
24. Cohen HW, Crandall JP, Hailpern SM, et al. Aspirin resistance associated with HbA1c and obesity in diabetic patients. J Diabetes Complications. 2008; 22(3):224-8.
25. Sane DC, McKee SA, Malinin AI, et al. Frequency of aspirin resistance in patients with congestive heart failure treated with antecedent aspirin. Am J Cardiol 2002; 90(8):893-5.
26. Tanrikulu A M, Ozben B, Koc M. Aspirin resistance in patients with chronic renal failure. J Nephrol.2011 Jan 17[Epub ahead of print].
27. Ikeda T, Taniguchi R, Watanabe S, et al. Characterization of the antiplatelet effect of aspirin at enrollment and after 2-year follow-up in a real clinical setting in Japan. Circ J.2010 74(6):1227-35.
28. Kour D, Tandon V, R, Kapoor B, et al. Aspirin Resistance J Med Edu & Res.2006; 8(2):116-7.
29. Bauriedel G, Skowasch D, Schneider M, et al. Antiplatelet effects of angiotensin-converting enzyme inhibitors compared with aspirin and clopidogrel:A pilot study with whole-blood aggregometry Am Heart J. 2003; 145:343-8.
30. Reavey-Cantwell JF, Fox WC, Reichwage BD, et al. Factors associated with aspirin resistance in patients premedicated with aspirin and clopidogrel for endovascular neurosurgery. Neurosurgery.2009; 64((5):890-5.
31. Pignone M, Alberts MJ, Colwell J A, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes. J Am Coll Cardiol.2010; 55(25):2878-86.
32. Neubauer H, Kaiser AF, Endres HG, et a 1. Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance--the BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy. BMC Med.2011 12:9:3.
33. El-Atat F, Sarkar K, Kodali V, et al. A randomized pilot trial for aggressive therapeutic approaches in aspirin-resistant patients undergoing percutaneous coronary intervention. Invasive Cardiol.2011; 23(1):9-13.
34. Stef G, Csiszar A, Ziangmin Z, et al. Inhibition of NAD(P)H oxidase attenuates aggregation of platelets from high-risk cardiac patients with aspirin resistance. Pharmacol Rep.2007; 59:428-36.
35. Poston RS, Gu J, White C, et al. Perioperative management of aspirin resistance after off-pump coronary artery bypass grafting:possible role for aprotinin. Transfusion.2008; 48:39S-46S.
1. Musunuru K, Post WS, Herzog W, et al. Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity:a potential mechanism for increased vascular disease. Circ Cardiovasc Genet.2010; 3(5):445-53.
2. Agundez JA, Martinez, Perez-Sala D, et al. Pharmacogenomics in aspirin intolerance. Curr Drug Metab.2009; 10(9):998-1008.
3. 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.
4. Fujiwara T, Ikeda M, Esumi K, et al. Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity. Pharmacogenomics J.2007; 7(6):395-403
5. Maree AO, Curtin RJ. Chubb A. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. Thromb Haemost.2005; 3(10):2340-5.
6. Pettinella C, Romano M, Stuppia L. Cyclooxygenase-1 haplotype C50T/A-842G does not affect platelet response to aspirin. Thromb Haemost. 2009101(4):687-90.
7. Li Q, Chen BL, Ozdemir V. Frequency of genetic polymorphisms of COX1, GPⅢa and P2Y1 in a Chinese population and association with attenuated response to aspirin. Pharmacogenomics J.2007; 8(6).
8. Kunicki TJ, Williams SA, Nugent DJ, et al. Lack of association between aspirin responsiveness and seven candidate gene haplotypes in patients with symptomatic vascular disease. Thromb Haemost.2009; 101(1):123-33.
9. Motovska Z, Kvasnicka J, Hajkova J. Platelet gene polymorphisms and risk of bleeding in patients undergoing elective coronary angiography:a genetic substudy of the PRAGUE-8 trial. Atherosclerosis.2010; 212(2):548-52.
10. Shi J, Misso NL, Duffy DL. Cyclooxygenase-1 gene polymorphisms in patients with different asthma phenotypes and atopy. Eur Respir J.2005; 26(2):249-56.
11. F u rst R, Blumenthal SB, Kiemer AK, et al. Nuclear factor-kappa B-independent anti-inflammatory action of salicylate in human endothelial cells:induction of heme oxygenase-1 by the c-jun N-terminal kinase/activator protein-1 pathway. J Pharmacol Exp Ther.2006;318(1):389-94.
12. Grosser N, Abate A, Oberle S, et al. Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochem Biophys Res Commun.2003; 308:956-60.
13. Pae HO, Lee YC, Chung HT. Heme oxygenase-1 and carbon monoxide: emerging therapeutic targets in inflammation and allergy. Recent Pat Inflamm Allergy Drug Discov.2008; 2(3):159-65.
14. Stocker R, Perrella MA. Heme oxygenase-1:a novel drug target for atherosclerotic diseases?. Circulation.2006; 114(20):2178-89.
15. Lavrovsky Y, Schwartzman ML, Levere RD, et al. Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc Natl Acad Sci U S A.1994; 91(13):5987-91.
16. Alam J, Cook JL. How many transcription factors does it take to turn on the heme oxygenase-1 gene? Am J Respir Cell Mol Biol.2007; 36(2):166-74.
17. Exner M, Minar E, Wagner O, et al. The role of heme oxygenase-1 promoter polymorphisms in human disease. Free Radic Biol Med.2004;37(8):1097-104.
18. Levonen AL, Vahakangas E, Koponen JK, et al. Antioxidant gene therapy for cardiovascular disease:current status and future perspectives. Circulation. 2008; 117(16):2142-50.
19. Kim TH, Chang HS, Park SM, et al. Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmatics. Clin Exp Allergy.2008; 38(11):1727-37.
20. Hu J, Miyatake F, Aizu Y, et al. Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population. Neurosci Lett. 1999; 17(277).
21. Tazawa R, Xu XM, Wu KK, et al. Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene. Biochem Biophys Res Commun.1994; 203(1):190-9.
22. Kranzhofer R, J. R. Aspirin resistance in coronary artery disease is correlated to elevated markers for oxidative stress but not to the expression of cyclooxygenase (COX) 1/2, a novel COX-1 polymorphism or the P1A(1/2) polymorphism. Platelets.2006; 17(3):163-9.
23. Maguire J, Thakkinstian A, Levi C, et al. J Stroke Cerebrovasc Dis. Impact of COX-2 rs5275 and rs20417 and GPIIIa rs5918 polymorphisms on 90-day ischemic stroke functional outcome:a novel finding.2011; 20(2):134-44.
24. McGeer PL, McGeer EG, Yasojima K. Expression of COX-1 and COX-2 mRNAs in atherosclerotic plaques. Exp Gerontol.2002; 37(7):925-9.
25. Fontana P, Dupont A, Gandrille S. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation.2003; 108(8):989-95.
26. Zee RY, Michaud SE, Diehl KA, et al. Purinergic receptor P2Y, G-protein coupled,12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism. Atherosclerosis.2008; 197(2):694-9.
27. Goodman T, Ferro A, Sharma P. Pharmacogenetics of aspirin resistance:a comprehensive systematic review. Br J Clin Pharmacol.2008; 66(2):222-32.
28. Nacmias B, Tedde A, Bagnoli S, et al. Lack of implication for CALHM1 P86L common variation in Italian patients with early and late onset Alzheimer's disease. J Alzheimers Dis.2010; 20(1):37-41.
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