【作者】 王斌；

【导师】 王任直； 马文斌； 杨义；

【作者基本信息】 中国协和医科大学 ， 神经外科学， 2009， 博士

【摘要】 目前在国际上脑卒中已经是继心血管病、肿瘤之后排名第三的致死原因,而在我国,根据卫生部统计资料,脑血管病已经超过心血管病,成为我国第二位的致死疾病,其中缺血性脑血管病占总数的80%左右。缺血性脑血管病作为一种可预防避免的疾病,在发现患病后,仍可通过认真执行二级预防措施、积极控制危险因素达到降低复发和致残的效果。病人对疾病危险因素的了解程度直接影响病人遵医嘱执行治疗方案的依从性从而影响治疗的效果。因此我们进行了本次调查,根据病人的具体情况指导病人控制危险因素和服药预防。另一方面,阿司匹林因为其抗血小板聚集地作用,已经成为预防缺血性脑卒中的一线药物,但是部分高危病人即使规律服用抗血小板药物,仍然在2年内再发血管意外事件。除了治疗依从性的影响外,阿司匹林在体内达不到治疗效果也是重要原因之一,被称之为“阿司匹林抵抗”(Aspirin Resistance)。国际上已有一些关于阿司匹林抵抗发生率和发生机制的研究,但是国内还缺乏系统研究。我们设计了抽样调查,研究中国缺血性脑血管病病人阿司匹林抵抗的发生率和临床因素的相关性;并进行基因检测,探索阿司匹林抵抗与相关基因单核苷酸多态性的关系和相关分子机制,为个体化的治疗方案提供策略。第一部分、缺血性脑血管病住院病人对危险因素的了解及控制情况的调查目的:研究当前缺血性脑血管病病人对疾病危险因素的了解及控制情况。方法:(1)调查2007年11月-2008年12月,在北京协和医院和北京宣武医院神经外科住院的315例症状性缺血性脑血管病病人,由专门人员进行问卷调查;(2)问卷内容主要包括两部分:人口社会学特征,是否存在和了解缺血性脑血管病的危险因素及自我控制情况;(3)入选标准:年龄＞18岁＜85岁、入院前已明确有多发TIAs或小范围缺血卒中、血管检查发现有脑血管狭窄、能配合调并征得其知情同意;(4)排除标准:发生过严重卒中后残留功能障碍生活不能自理者、不能配合调查者或不愿参加调查者;(5)采用SPSS 11.5(Statistical Package for Social Sciences,Lead Technologies,Inc.,Chicago,IL,USA)对结果进行统计学分析。结果:(1)调查315例缺血性脑血管病病人,其中男176例,女139例,年龄38-80岁,平均60.03±11.97岁;(2)病人危险因素的分布:运动缺乏(68.6%)、吸烟(65.7%)、肥胖(65.7%)、高血压(60.0%)、饮酒(51.4%)、高血脂(40.0%)、糖尿病(37.1%)、缺血家族史(36.8%)、冠心病(28.6%);(3) 68.6%(261/315)的病人承认知道卒中是可以预防的疾病;91.4%(288/315)的病人承认知道至少一种卒中的危险因素;(4)危险因素中认知度最高的是运动不足(68.6%,216/315),其次是吸烟(65.7%,207/315)、肥胖(65.7%,207/315)、高血压(60%,189/315)、饮酒(51.4%,162/315)、高血脂(40%,126/315)、糖尿病(37.1%,117/315)、中风家族史(36.8%,116/315)、冠心病(28.6%,90/315);(5) Binary Logistic Regression分析发现,教育程度和体育运动对危险因素的了解程度有显著影响,OR值分别为13.460(95%CI,6.249～28.994)和11.761(95%CI,4.361～31.716)。结论:目前国内病人对危险因素的了解和控制情况还很不理想,需要加大宣传力度,并针对性的对病人做出指导。第二部分、缺血性脑血管病病人阿司匹林治疗依从性及其影响因素的调查目的:回顾性研究服用阿司匹林的缺血性脑血管病病人服药依从性情况,分析影响依从性的因素。方法:(1)对2007年11月-2008年12月间在北京协和医院和北京宣武医院神经外科住院的症状性缺血性脑血管病病人进行阿司匹林服用依从性调查;(2)纳入和排除标准同第一部分(3)对接受调查的病人进行随访观察依从性变化;(4)对调查对象的人口社会学特征和药物治疗依从性进行描述分析;对药物治疗依从性影响因素Logistic分析;观察分析入院前后病人服药依从性的变化。结果:(1)以入院前严格按照医嘱服药天数大于总天数的80%为依从性好,共计191例,占总数60.6%,依从性不佳的病人中完全停止服药的有47例,占总数的14.9%;(2)病人的居住地、教育程度、家庭收入、职业情况、医疗保险、体育锻炼、吸烟、自己或亲朋是医务工作者等因素在依从性不同的两组病人中的分布有明显差异;(3)多因素分析(Binary Logistic Regression)发现仅有居住地(农村/城市)和是否自己或亲朋为医务工作者与服药依从性有显著关系,OR值分别为5.328(95%CI,3.157～8.994)和2.727(95%CI,1.327～5.603);(4)出院后随访服药依从性好的随访病人有201例,占随访总数的79.1%,其中完全停止服药者6例,占随访病人总数的3.5%,依从性较入院前有明显提高;(5)患者自述依从性不佳的原因有:对疾病认识不够、认为疾病已治愈、主观认为身体健康、认为药物无效、经济原因、工作原因、就医困难等。结论:(1)入院前病人总体服药依从性较低;(2)出院后依从性有所提高;(3)需要加强疾病教育和医患沟通。第三部分、缺血性脑血管病病人阿司匹林抵抗的分布和相关基因多态性的研究目的:通过血栓弹力图检测研究缺血性脑血管病病人服用阿司匹林后血小板抑制率的改变,筛选阿司匹林抵抗的病人,同时检测相关基因SNP多态性与阿司匹林抵抗的关系,从而进一步探索阿司匹林抵抗的机制,在临床中实现治疗措施的个体化,减少血栓事件的发生。方法:(1) 2007年11月-2008年12月,在北京协和医院和北京宣武医院神经外科住院的315例症状性缺血性脑血管病病人挑选愿意参加研究的病人;(2)入选标准:年龄＞18岁＜85岁;入院前至少连续按量服用阿司匹林7天以上;已明确有多发TIAs或小范围缺血卒中、血管检查发现有脑血管狭窄的患者;能配合调查;患者对本研究知情同意(3)排除标准:发生过严重卒中后残留功能障碍,生活不能自理者;血小板计数大于450×109/L或小于100×109/L者;血红蛋白小于80g/L者;骨髓增生异常综合征、恶性浆细胞病患者;近期有大外科手术史者;近一周使用噻氯匹定、传统非甾体抗炎药及肝素,低分子肝素,华法令者;不能配合调查者和不愿参加调查者。(4)使用TEG血小板图检测患者服用阿司匹林后血小板被抑制情况,将病人分为阿司匹林抵抗和阿司匹林敏感组;(5)使用SNPStream技术检测阿司匹林抵抗相关基因的SNP位点情况,探索阿司匹林抵抗与相关基因SNP的关系。(6)使用SPSS 11.5、haploview 4.1和在线SNPstats,进行统计学和生物遗传学分析。结果:(1)经筛选共纳入病人220例。其中男性171例,女性49例,年龄从33岁-80岁,平均年龄58.7±10.4岁;(2)使用血栓弹力图(TEG)技术共检测出阿司匹林抵抗(AR)19例,占总数的8.64%;(3)统计学分析发现年龄、WBC、RBC、Hgb、PLT、Alb、TG的水平在AS组高于AR组,但无统计学差异(P＞0.05);ALT、TCH、HDL、LDL、CRP、APTT、Fib的水平在在AR组高于AS组,但无统计学差异(P＞0.05);两组间男女性比例无统计学差异(P＞0.05);AR组的高血压患病率低于AS组(P=0.025),其他危险因素的分布无统计学差异(P＞0.05);(4) SNPStream检测发现PTGS1-rs3842788(P＜0.005)、ITGA2B-rs5911(P＜0.001)、P2RY1-rs16864613(P＜0.001)、P2RY12-rs6809699(P＜0.001)这四个位点等位基因分布频率在AR组和AS组病人中分布有显著性差异(P＜0.005);(5)非条件Logistic Regression;分析发现PTGS1-rs3842788、ITGA2B-rs5911、P2RY1-rs16864613、P2RY12-rs6809699与AR的发生相关结论:(1)本研究对220例服用阿司匹林预防卒中的缺血性脑血管病病人使用TEG血小板图检测血小板功能,发现AR19例,发生率为8.64%。(2)在AR组和AS组病人间,除了高血压的患病率不同,其他危险因素、临床状况和生化检测结果没有显著差异。(3) PTGS1-rs3842788、ITGA2B-rs5911、P2RY1-rs16864613、P2RY12-rs6809699的多态性与AR的发生相关。更多还原

【Abstract】 BackgroudStroke is currently the third cause of death in the world,following cardiovascular disease and cancer,while in China,according to the Ministry of Health’s report, cerebrovascular disease has become China’s second fatal disease,in which,ischemic cerebrovascular disease accounts for about 80%of the total.Ischemic cerebrovascular disease as a disease that can be prevented,the recurrence and disability rate could be reduced by seriously implementing the secondary prevention measures and control risk factors.Patients’ knowledge with risk factors of diseases directly affects the level of understanding of the implementation of the treatment and the compliance to the medical prescription and then influences the effectiveness of treatment. Therefore,we carried out the survey,to guide those patients’ contolling risk factors and choosing prevention medication in accordance with the specific circumstances.On the other hand,aspirin because of its role in anti-platelet aggregation and has become the first-line drugs in the prevention of ischemic stroke,but even if some high-risk patients taking anti-platelet drugs regularly,recurrent vascular accident still could happen within 2 years.In addition to the impact of treatment compliance,the aspirin in the body could not achieve the therapeutic effect is one of the important reasons,which was called "aspirin resistance"(AR).There have been some studies on the incidence of aspirin resistance and the mechanism,but there was still lack of systematic research about Chinese patients.We designed a sample survey,to study the incidence of aspirin resistance and clinical factors of relevance in Chinese patients with ischemic cerebrovascular disease;and developed genetic testing,to explore aspirin resistance-related genes’ single nucleotide polymorphisms and related molecular mechanism,provided strategy for the individual treatment programs. Part 1.Knowledge and conrolling of risk factors in Chinese lschemic Cerebrovascular Diseases PatientsObject:The current study aims to investigate the patients’ knowledge and controlling of risk factors of ischemic cerebrovascular diseases.Method:(1) During November 2007 to December 2008,315 cases of symptomatic ischemic cerebrovascular disease patients were admitted in Peking Union Medical College Hospital and Beijing Xuanwu Hospital,which were Surveyed by specialized staff.(2) The questionnaire had two sections:socio-demographics characteristics, awareness of risk factors of stroke and self-control;(3) Inclusion criteria:18-85 years old,had TIAs or minor stroke before admission,had cerebrovascular stenosis comfirmed by vascular exam,cooperated with the investigation and with the informed consent;(4) Exclusion criteria:had serious residualpost-stroke dysfunction and could not take care of themselves,can not cooperate with the investigation or who do not want to participate in the investigation;(5) Results were analysised by SPSS 11.5(Statistical Package for Social Sciences,Lead Technologies,Inc.,Chicago,IL,USA).Result:(1) Of 315 participants,176 male and 139 were females with a mean age 60.03±11.97;(2) The distribution of risk factors:Physical inactivity(68.6%),smoking (65.7%),obesity(65.7%),hypertension(60.0%),alcoholism(51.4%),hyperlipidemia (40.0%),diabetes(37.1%),ischemic family history(36.8%),coronary heart disease (28.6%);(3) 68.6%(261/315) of participants admitted to know the disease can be prevented;91.4%(288/315) of participants admitted that they were aware of at least one risk factor for stroke;(4) Among risk factors,physical inactivity was ranked as the most common (68.6%,216/315),followed by smoking(65.7%,207/315),obesity(65.7%,207/315), hypertension(60%,189/315),alcohol(51.4%,162/315),high blood lipids(40%, 126/315),diabetes(37.1%,117/315),family history of stroke(36.8%,116/315),coronary heart disease(28.6%,90/315); (5) Binary Logistic Regression analysis showed that the factors related to the level of awareness were determined to be:levels of education and sports,OR values were 13.460(95%CI,6.249～28.994) and 11.761(95%CI,4.361～31.716).Conclusion:At present,patients’ awareness of risk factors and controlling situation is far from ideal,that call for more public education and make the patient-specific guidance.Part 2.Ischemic Cerebrovascular Disease Patients’ Aspirin Treatment Compliance and Its Impact FactorsObject:To explore the ischemic cerebrovascular disease patients’ compliance to aspirin treatment and the influential factors.Method:(1) Participants:symptomatic ischemic cerebrovascular disease patients were admitted in Peking Union Medical College Hospital and Beijing Xuanwu Hospital during November 2007 to December 2008.(2) Inclusion and exclusion criteria were the some to the Part 1.(3) Investigated the participants’ compliance and carried out follow-up to observe changing of comliace;(4) Statistical analysis participants socio-demographics characteristics and compliance to aspirin;relationship assessments of compliance were performed utilizing logistic regression;observe and analyze the patients admitted to hospital before and after changes in medication compliance.Result:(1) 191 cases,accounting for 60.6%of all patients had good compliance before admission;47 cases completely ceased medication,accounting for 14.9 percent of the total number;(2) The patient’s place of residence,educational attainment,household income, occupational situation,health insurance,physical activity,smoking,as health care workers or had friends or relatives as health care workers were different distribution in both groups and had significant differences;(3) Multivariate analysis(Binary Logistic Regression) found that only place of residence(rural/urban) and whether their own or friends and relatives as medical workers had significant relationship with drug compliance,OR values were 5.328(95% CI,3.157～8.994) and 2.727(95%CI,1.327～5.603);(4) Post-discharge follow-up to medication compliance of patients found good compliance in 201 cases,accounting for 79.1%of the total number of follow-up, complete cessation of medication in 6 patients,accounted for 3.5%of the total number of follow-up patients,compliance had significantly improved compared to pre-hospital;(5) Patient’s self-report reasons for poor compliance were:inadequate understanding of disease,consider the disease has been cured,perceived good health and that the drug does not work,for economic reasons,the work reasons and difficulties in hospitalizing.Conclusion:(1) Patients with lower drug compliance pre-hospital;(2) Compliance improved after discharge;(3) The need to strengthen disease education and patient communication.Part 3.The Distribution of Aspirin Resistance and Related Gene Polymorphism in Ischemic Cerebrovascular Disease PatientsObject:Utilize thromboelastography to screen aspirin-resistance in ischemic cerebrovascular disease patients,and detection of related gene SNP polymorphisms to explore its relationship to aspirin resistance,in order to further explore the mechanism of aspirin resistance and achieve individualized treatment to reduce the incidence of thrombosis.Method:(1) During November 2007 to December 2008,315 cases of symptomatic ischemic cerebrovascular disease patients were admitted in Peking Union Medical College Hospital and Beijing Xuanwu Hospital,from which chose the patients willing to participate in the study.(2) Inclusion criteria:18-85 years old,at least consecutively used aspirin for 7 days before admission,had TIAs or minor stroke before admission,had cerebrovascular stenosis comfirmed by vascular exam,cooperated with the investigation and with the informed consent.(3) Exclusion criteria:had serious residualpost-stroke dysfunction and could not take care of themselves,platelet count greater than 450×10~9/L or less than 100×10~9/L,hemoglobin less than 80g/L;patients with malignant plasma cells or myelodysplastic syndrome,recent history of major surgery,used of Ticlopidine, traditional non-steroidal anti-inflammatory drugs and heparin,low molecular weight heparin,warfarin in the past weeks,can not cooperate with the investigation or who do not want to participate in the investigation;(4) Utilized TEG to detect patients’ platelet function and divided them to AR group or AS group;(5) Utilized SNPStream technique to detect AR related gene SNPs distribution and explore their relationship;(6) Using SPSS 11.5,haploview 4.1 and online tool SNPstats to conduct statistical and biological genetics analysis.Result:(1) 220 patients participated in this study,171 male and 49 were females with a mean age 58.7±10.4;(2) Using of thromboelastography(TEG) technology,19 cases were diagnosed had aspirin resistance(AR),accounting for 8.64%of the total number;(3) Statistical analysis showed that age,WBC,RBC,Hgb,PLT,Alb,TG levels were higher in the AR group than in the AS group,but no significant difference(P>0.05); ALT,TCH,HDL,LDL,CRP,APTT,Fib levels of the AR group were higher than in the AS group,but no significant difference(P>0.05);the proportion of males and females between the two groups no significant difference(P>0.05);in AR group the prevalence of hypertension was lower than in the AS group(P=0.025),the distribution of other risk factors were no significant difference in two groups(P>0.05);(4) SNPStream detection showed that:allele frequency distribution between AS and AR group were significantly different at four SNP sites,these were PTGSl-rs3842788(P<0.005),ITGA2B-rs5911(P<0.001),P2RY1-rs16864613(P <0.001),P2RY12-rs6809699(P<0.001);(5) Unconditioned Logistic Regression analysis showed that PTGS1-rs3842788, ITGA2B-rs5911,P2RY1-rs16864613,P2RY12-rs6809699 were associated with the occurrence of AR.Conclusion:(1) In this study the occurrence rate of AR was 8.64%;(2) Between AS and AR group,clinical status and biochemical test results no significant differences had no significant differences except the prevalence rate of hypertension;(3) Morphrism of PTGS1-rs3842788,ITGA2B-rs5911, P2RY1-rs16864613 and P2RY12-rs6809699 were associated with the occurrence of AR.更多还原