中国冠心病患者介入术后血小板高反应性的相关危险因素分析

发布时间：2018-06-21 18:05

本文选题：血小板内皮聚集受体1 + 血小板反应性　；参考：《北京协和医学院》2017年博士论文

【摘要】：背景:阿司匹林联合氯吡格雷双联抗血小板治疗是急性冠脉综合征患者或行经皮冠状动脉介入术患者的治疗基石。然而,临床实践发现,在抗血小板治疗中血小板反应性存在个体差异。一部分患者在接受阿司匹林或氯吡格雷治疗后血小板不能获得充分抑制,易导致血小板高反应性。研究表明遗传因素即基因多态性在抗血小板疗效个体差异中起到了至关重要的作用。血小板内皮聚集受体1(Platelet Endothelial Aggregation Receptor 1,PEAR1)是一种表达在血小板膜表面的跨膜蛋白,在血小板聚集中起着重要作用。本研究的目的是探讨分析编码PEAR1蛋白的PEAR1基因多态性对服用阿司匹林和氯吡格雷双联抗血小板治疗的中国冠心病患者冠脉介入术后血小板反应性的影响。方法:本研究纳入2011年11月至2013年3月于我院行经皮冠状动脉介入术的冠心病患者,所有患者均服用阿司匹林和氯吡格雷双联抗血小板治疗。利用血栓弹力图法检测二磷酸腺苷(adenosine diphosphate,ADP)刺激下的血小板反应性,结果记录为血小板聚集抑制率(inhibition of platelet aggregation,IPA)。IPA 小于 30%定义为治疗下血小板高反应性(high on-treatment platelet reactivity,HTPR);IPA大于70%定义为治疗下血小板低反应性(low on-treatment platelet reactivity,LTPR)。依据血小板反应性将患者分为HTPR组和LTPR组,采用病例对照研究模式分析基因多态性对血小板反应性的影响。依据已发表文献报道和人类基因组单倍体型网站(HAPMAP,http://hapmap.ncbi.nlm.nih.gov/),利用Haploview 4.2软件筛选出本研究待分析的PEAR1基因单核苷酸多态性位点(single nucleotide polymorphism,SNP)。利用改良的多重链接酶检测反应测定PEAR1基因SNPs的分型,比较SNPs次要等位基因在HTPR和LTPR两组间携带频率的差异。结果:204名患者存在血小板高反应性,201名患者存在血小板低反应性。基于文献报道和HAPMAP分析结果,共16个PEAR1 SNPs纳入本研究进行基因分型。16个SNPs中发现有5个SNP与ADP刺激下的血小板聚集显著相关。单因素分析发现在显性模型中rs11264580的C次要等位基因(p=0.033),rs2644592的G次要等位基因(p=0.048),rs3737224的T次要等位基因(p=0.033)、rs41273215的T次要等位基因(p=0.025)以及单倍体型分析中C-G-T-T-C(p=0.034)在HTPR组携带率显著高于LTPR组,表明与血小板高反应性显著相关;在隐性模型中rs57731889 TT纯合子基因型(p=0.009)以及单体型分析中T-A-C-C-T(p=0.009)在LTPR组携带率显著高于HTPR组,表明与血小板低反应性显著相关。使用logistic多因素回归模型校正混杂因素进一步分析后显示rs41273215的T次要等位基因(p=0.038)是血小板高反应性的一个独立预测因子,而rs57731889的TT纯合子(p=0.003)则是血小板低反应性的独立预测因子。结论:(1)PEAR1基因多态性与中国冠心病患者ADP刺激下的血小板反应性密切相关;(2)PEAR1基因多态性的不同位点对血小板功能的影响明显不同;(3)rs41273215导致血小板高反应性,rs57731889导致血小板低反应性。背景:血栓形成是引发急性冠状动脉综合征的核心原因。血小板是血栓的最主要组成成分,其黏附、活化、聚集在血栓形成中起着至关重要的作用,因此抗血小板治疗已成为防治血栓形成、减少临床不良事件发生的的重要基石。临床实践发现,抗血小板疗效在患者中存在个体差异,部分患者对阿司匹林或氯吡格雷存在抵抗现象,易导致疗效不佳、发生临床不良缺血性事件。血小板内皮聚集受体l(Platelet Endothelial Aggregation Receptor 1,PEAR1)是一种表达在血小板膜表面的跨膜蛋白,在血小板聚集中起着重要作用。本研究的目的是探讨分析编码PEAR1蛋白的PEAR1基因多态性对中国急性心机梗死患者冠状动脉介入术后1年的临床预后影响。方法:本研究纳入2011年11月至2013年3月于我院行冠状动脉介入术的急性心肌梗死患者,所有患者均服用阿司匹林和氯吡格雷双联抗血小板治疗。本课题组前期工作中发现的与血小板高反应性相关的PEAR1基因单核苷酸多态性位点(single nucleotide polymorphism,SNP)被纳入本研究中,以探讨它们对临床预后的影响,由于本研究为探索性研究,故SNP的P值只要小于0.1即被纳入。利用改良的多重链接酶检测反应测定PEAR1基因SNPs的分型。术后通过再入院记录、门诊及电话进行12个月的临床随访,随访事件包括全因死亡,心原性死亡,心肌梗死,非计划血运重建和支架内血栓。复合缺血事件定义为包括心原性死亡、心肌梗死、非计划血运重建和支架内血栓的复合临床终点。结果:依据纳入排除标准,共647名急性心肌梗死患者被纳入本研究。依据课题组前期研究结果,6个与血小板高反应性相关的PEAR1 SNPs:rs11264580、rs2644592、rs3737224、rs41273215、rs56260937、rs822442 被纳入本研究。在 1 年随访中,共66人(10.2%)发生不良临床事件:全因死亡8例(1.2%)、心原性死亡4例(0.6%),心肌梗死6例(0.9%),因缺血驱动的血运重建61例(9.4%),未随访到发生支架内血栓事件。在隐性模型分析中,相较主要等位基因携带者,rs56260937次要等位基因TT纯合子携带者发生因缺血驱动的血运重建发生率显著增高(16.7%vs 8.6%,P=0.034)。进一步使用多因素Cox回归分析校正混杂因素后,结果表明rs56260937是血运重建的独立危险因素(HR=2.09,95%CI 1.07-4.06,p=0.031)。结论:(1)PEAR1基因多态性与中国急性心肌梗死患者介入术后1年的临床预后显著相关;(2)rs56260937次要等位基因TT纯合子基因型显著增加血运重建事件发生率;(3)进行PEAR1基因检测,未来有可能用于指导临床个体化抗血小板治疗,以期改善患者临床预后。背景:抗血小板治疗是急性冠状动脉综合征的治疗基石。然而临床实践发现,部分患者对抗血小板药物存在抵抗现象,易导致治疗下血小板高反应性((high on-treatment platelet reactivity,HTPR)。目前,国内外已有诸多研究表明临床因素对患者服用药物的反应性有显著影响,基于此,我们的研究旨在利用临床常用指标,筛选出与血小板高反应性相关的临床危险因素,并构建血小板高反应性临床风险评分。该评分的构建将有助于临床医师对患者血小板反应性做出快速全面评估,从而给予针对性的个体化抗血小板治疗。方法:本研究纳入2013年1月至2013年12月在中国医学科学院阜外医院接受经皮冠状动脉介入术且服用阿司匹林和氯吡格雷双联抗血小板治疗的急性冠状动脉综合征患者。利用血栓弹力图检测二磷酸腺苷(adenosine diphosphate,ADP)刺激下的血小板反应性。血小板高反应性定义为ADP刺激下的血小板-纤维蛋白凝块强度(MAADP)大于47毫米。纳入临床常用指标,采用单因素和多因素logistic回归分析,筛选出与血小板高反应性独立相关的危险因素。对于连续性临床变量,在分析前,依据临床常用界值将其转换为二分类变量。筛选出的与血小板高反应性独立相关(P0.05)的临床危险因素被纳入风险评分模型,并依据比值比(OR)大小对临床因素进行赋分,由此构建风险评分。对纳入本研究的患者追踪随访介入术后2年不良心脑血管事件包括全因死亡,心原性死亡,心肌梗死,非计划血运重建、支架内血栓和脑卒中。结果:依据纳入排除标准,共2511例行经皮冠状动脉介入治疗的急性冠状动脉综合征患者纳入本研究。共有781名(31.10%)患者存在血小板高反应性。单因素和多因素logistic回归分析显示共有五个临床因素与血小板高反应性独立相关,并依据OR值大小进行相应赋分:肾功能减低(Scr133umol/L,OR=3.06,95%CI 1.28-7.32)赋 3 分;女性(OR=2.84,95%CI 2.24-3.59)赋 2 分;糖尿病(OR=1.61,95%CI 1.33-1.95)赋1;血小板增多(30×109,OR=1.55,95%CI1 1.07-2.25)赋1分;使用质子泵抑制剂(OR=1.25.95%CI 1.02-1.53)赋1分;由此构建了 0-8分的血小板高反应性临床风险评分。依据患者得分,将患者分为低危组0-2分、中危组3-5分和高危组6-8分。三组血小板反应性(TEG-MAADP)分别为 33.88± 17.75mm,45.69± 17.05mm和 50.90± 17.80mm;分别有 587(26.95%),192(58.18%)和 2(66.67%)例患者存在血小板高反应性,三组间存在显著差异(P0.001)。但研究结果显示无论是单一事件还是复合临床终点主要不良心脑血管事件的发生率在三组间均无显著差异。结论:(1)临床因素是导致血小板高反应性的重要原因之一,临床风险评分越高的患者越有可能表现出血小板高反应性;(2)临床风险评分有助于快速识别可能存在血小板高反应性患者,从而指导个体化抗血小板治疗,且无需额外检测、花费;(3)本研究构建的临床风险因素评分仅能够有效地预测血小板高反应性,对介入术后2年的临床不良事件不能进行有效预测。
[Abstract]:Background: aspirin combined with clopidogrel is the cornerstone of the treatment of patients with acute coronary syndrome or percutaneous coronary intervention. However, clinical practice has found that there are individual differences in platelet reactivity in antiplatelet therapy. Some patients receive small blood levels after the treatment of aspirin or clopidogrel. The study showed that genetic polymorphisms played a vital role in the individual difference in antiplatelet efficacy. The platelet endothelial aggregation receptor 1 (Platelet Endothelial Aggregation Receptor 1, PEAR1) is a transmembrane protein expressed on the surface of the platelet membrane, The purpose of this study was to investigate the effect of the PEAR1 gene polymorphism of the encoded PEAR1 protein on platelet reactivity after coronary intervention in Chinese coronary heart disease patients with aspirin and clopidogrel antiplatelet therapy. Methods: This study was included in my study from November 2011 to March 2013. All patients were treated with aspirin and clopidogrel antiplatelet therapy in patients who underwent percutaneous coronary intervention. Platelet reactivity under adenosine diphosphate (adenosine diphosphate, ADP) was detected by thrombus mapping. The results were recorded as platelet aggregation inhibition rate (inhibition of platelet aggregat). Ion, IPA).IPA less than 30% is defined as treatment of platelet hyperresponsiveness (high on-treatment platelet reactivity, HTPR); IPA greater than 70% is defined as thrombocytopenia under treatment (low on-treatment platelet). The effect of polymorphism on platelet reactivity. Based on published literature and human genome HAPMAP (http://hapmap.ncbi.nlm.nih.gov/), the PEAR1 single nucleotide polymorphic loci (single nucleotide polymorphism, SNP) in this study were screened using Haploview 4.2 software. The improved multiplicity was used. The genotyping of the PEAR1 gene SNPs was measured by the linked enzyme detection reaction. The differences in the frequency of the SNPs secondary alleles between the HTPR and LTPR two groups were compared. Results: 204 patients had platelet hyperresponsiveness and 201 patients had thrombocytopenia. Based on literature and HAPMAP analysis, a total of 16 PEAR1 SNPs were included in this study to carry out genes. In the.16 SNPs, 5 SNP were found to be significantly associated with platelet aggregation stimulated by ADP. Single factor analysis found that the C secondary allele (p=0.033), rs2644592's G secondary allele (p=0.048), rs3737224 T secondary alleles (0.033), minor alleles, and haploid genes were found in the dominant model. In somatotype analysis, the carrying rate of C-G-T-T-C (p=0.034) in group HTPR was significantly higher than that in group LTPR, indicating a significant correlation with platelet hyperresponsiveness. In the recessive model, the rs57731889 TT homozygote genotypes (p=0.009) and the T-A-C-C-T (p=0.009) in the haplotype analysis were significantly higher in the LTPR group than that in the HTPR group, indicating a significant correlation with the platelet hyper reactivity. Logistic multifactor regression model was used to correct confounding factors and further analysis showed that the T secondary allele (p=0.038) was an independent predictor of platelet hyperresponsiveness, and rs57731889 TT homozygote (p=0.003) was an independent pretest factor for platelet hypo reactivity. Conclusion: (1) the polymorphism of PEAR1 gene and the Chinese crown. Platelet reactivity is closely related to ADP stimulation in patients with heart disease; (2) the effect of different loci of PEAR1 gene polymorphism on platelet function is distinct; (3) rs41273215 leads to platelet hyperresponsiveness, and rs57731889 leads to thrombocytopenia. Background: thrombosis is the core cause of acute coronary syndromes. Platelets are The most important component of thrombus, its adhesion, activation and aggregation plays a vital role in the formation of thrombus, so antiplatelet therapy has become an important cornerstone for preventing thrombosis and reducing the occurrence of adverse events. Clinical practice has found that there are individual differences in antiplatelet efficacy in patients, and some patients with aspirin or Clopidogrel has a resistance phenomenon, which leads to poor efficacy and adverse clinical ischemic events. Platelet endothelial aggregation receptor L (Platelet Endothelial Aggregation Receptor 1, PEAR1) is a transmembrane protein expressed on the surface of platelets and plays an important role in platelet aggregation. The purpose of this study is to explore the analysis of coded PE. The effect of the PEAR1 gene polymorphism of AR1 protein on the clinical prognosis of 1 years after coronary intervention in patients with acute myocardial infarction in China. Methods: This study was included in patients with acute myocardial infarction in our hospital from November 2011 to March 2013. All patients were treated with aspirin and clopidogrel. The PEAR1 gene polymorphic loci (single nucleotide polymorphism, SNP) associated with platelet hyperresponsiveness (SNP), which was associated with platelet hyperresponsiveness, was included in this study to explore their effects on the clinical prognosis. Because this study is an exploratory study, the P value of SNP is incorporated as long as less than 0.1 of the P value is included. The relinked enzyme detection reaction was used to determine the type of PEAR1 gene SNPs. After readmission, the clinic and telephone were followed up for 12 months, including all causes of death, cardiac death, myocardial infarction, unplanned revascularization, and stent thrombosis. Complex ischemic events were defined as cardiogenic death, myocardial infarction, and unplanned. Results: a total of 647 patients with acute myocardial infarction were included in this study according to the exclusion criteria. According to the results of the previous study group, 6 PEAR1 SNPs:rs11264580, rs2644592, rs3737224, rs41273215, rs56260937, and rs822442 related to platelet hyperresponsiveness were included in this study. During the 1 year follow-up, 66 people (10.2%) had adverse clinical events: 8 cases of total death (1.2%), 4 cardiac death (0.6%), 6 myocardial infarction (0.9%), 61 cases (9.4%) due to ischemia driven blood transport and 61 cases (9.4%) without follow-up. In the recessive model analysis, the secondary allele of rs56260937 was compared with the main allele carriers. The incidence of blood transport reconstruction driven by TT homozygous carriers increased significantly (16.7%vs 8.6%, P=0.034). Further using multiple factor Cox regression analysis to correct confounding factors, the results showed that rs56260937 was an independent risk factor for revascularization (HR=2.09,95%CI 1.07-4.06, p=0.031). Conclusion: (1) the polymorphism of PEAR1 gene and the urgency of China The clinical prognosis of 1 years after interventional therapy in patients with myocardial infarction is significantly related; (2) the rs56260937 secondary allele TT homozygous genotype significantly increases the incidence of revascularization events; (3) PEAR1 gene detection, and the future may be used to guide clinical individualized antiplatelet therapy in order to improve the patient's clinical prognosis. Background: antiplatelet therapy Therapy is the cornerstone of the treatment of acute coronary syndrome. However, clinical practice has found that some patients have resistance to platelets, which may lead to high on-treatment platelet reactivity (HTPR). At present, many studies have shown that the clinical factors are responsive to the drug response to patients. Significantly, based on this, our study aims to use clinical indicators to screen out clinical risk factors associated with platelet hyperresponsiveness and to construct a clinical risk score for platelet hyperresponsiveness. The construction of this score will help clinicians to make a rapid and comprehensive assessment of the patient's platelet reactivity, thus giving specific targets. Individualized antiplatelet therapy. Methods: This study was included in patients with acute coronary syndromes from January 2013 to December 2013 at the Fuwai Hospital of the Chinese Academy of Medical Sciences, who received percutaneous coronary intervention and taken aspirin and clopidogrel antiplatelet therapy. The blood thrombus elasto map was used to detect adenosine two (adenosine DIPH). Osphate, ADP) stimulated platelet reactivity. The platelet hyperresponsiveness is defined as the platelet fibrin clot intensity (MAADP) greater than 47 mm under the stimulation of ADP. Inclusion of clinical indicators, using single factor and multifactor logistic regression analysis, screening risk factors independent of platelet hyperresponsiveness. For continuous clinical trials Variables, before analysis, were converted to two categorical variables according to the clinical common boundary value. The clinical risk factors that were screened for independent platelet hyperresponsiveness (P0.05) were included in the risk score model, and the clinical factors were assigned according to the ratio Ratio (OR) size, and the risk score was constructed. The follow-up follow-up of the patients included in this study was followed up. 2 years of adverse cardiac and cerebrovascular events after intervention included all causes of death, cardiac death, myocardial infarction, unplanned blood revascularization, stent thrombosis and stroke. Results: according to the inclusion criteria, 2511 patients with acute coronary syndromes with percutaneous coronary intervention were included in this study. A total of 781 (31.10%) patients were present. Platelet hyperresponsiveness. Single factor and multiple factor Logistic regression analysis showed a total of five clinical factors independent of platelet hyperresponsiveness, and according to the value of OR values: renal dysfunction (Scr133umol/L, OR=3.06,95%CI 1.28-7.32) 3; women (OR= 2.84,95%CI 2.24-3.59) 2; diabetes (OR=1.61,95%CI 1.). 33-1.95) Fu 1; thrombocytosis (30 x 109, OR=1.55,95%CI1 1.07-2.25) 1 points; 1 points using proton pump inhibitor (OR=1.25.95%CI 1.02-1.53); thus, a 0-8 point platelet hyperreactive clinical risk score was constructed. According to the patient's score, the patients were divided into low risk group 0-2, 3-5 in middle risk group and 6-8 in high-risk group. Three platelets reaction. TEG-MAADP was 33.88 + 17.75mm, 45.69 + 17.05mm and 50.90 + 17.80mm, respectively, there were 587 (26.95%), 192 (58.18%) and 2 (66.67%) patients with high reactivity of platelets. There were significant differences between the three groups (P0.001). But the results showed that the major adverse cardiac and cerebrovascular events occurred in either single or compound clinical endpoint. There is no significant difference in the rate between the three groups. Conclusion: (1) the clinical factors are one of the important causes of the hyperresponsiveness of platelets. The more patients with higher clinical risk score, the more likely to show the hyperreactivity of platelets; (2) the clinical risk score is helpful for the rapid identification of patients with high responsiveness to the platelets, thus guiding the individualized antiplatelet. Treatment, without additional detection, costs; (3) the clinical risk factor score constructed in this study can only effectively predict the hyperresponsiveness of the platelets and can not effectively predict the clinical adverse events of the 2 year after intervention.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R541.4

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