冠心病患者阿司匹林抵抗与血栓素B2的相关性研究

目的:观察冠心病(CGD)患者阿司匹林治疗前后血浆血栓素B2(TXB2)水平的变化,探讨其与阿司匹林抵抗(AR)的关系.方法:采用酶联免疫吸附法测定60例CHD患者(CHD组)及20例健康人(正常对照组)血浆TXB2水平.60例CHD患者接受阿司匹林(100 mg,qd)等治疗,2周后复测血浆TXB2水平,并采用比浊法分别测定由二磷酸腺苷、花生四烯酸诱导的血小板聚集率(PAG).根据PAG将CHD组分为AR亚组和阿司匹林敏感(AS)亚组.结果:CHD患者治疗后血浆TXB2水平比治疗前明显降低(P＜0.01),但仍高于正常对照组(P＜0.01).入选60例CHD患者中有8例(13.3%)存在AR.AR亚组血浆TXB2水平高于AS亚组(P＜0.01).结论:CHD患者阿司匹林治疗中AR发生率为13.3%.阿司匹林治疗2周后,AR患者血浆TXB2水平仍较高,可能与AR相关.血浆TXB2可作为CHD患者阿司匹林治疗中早期识别AR的指标之一.     

阿司匹林抵抗的研究现状

阿司匹林抵抗即阿司匹林不能减少血小板血栓素A2的生成并因此引起血小板活化和聚集。阿司匹林抵抗的可能原因包括用量不当、药物相互作用、环氧合酶-1的遗传多态性和涉及血栓素生物合成的其他基因、血栓素生物合成的非血小板源性因素的上调和血小板更新增强。阿司匹林抵抗程度的增强可能与心血管事件风险的增加独立相关。目前还没有一种精确定性和定量分析的方法来检测阿司匹林的抗血小板功能异常,从而解释生物化学的阿司匹林抵抗。今后的研究旨在准确定义阿司匹林抵抗、开发可靠的检测方法并确定相关心血管事件的发生风险。     

阿司匹林抵抗研究进展

阿司匹林为最常用的抗血小板药物,在心脑血管疾病的一级预防和二级预防中有重要作用.临床上将应用阿司匹林治疗不能充分抑制血小板聚集功能而导致临床血栓事件发生的现象称之为阿司匹林抵抗(aspirin resistance,AR)[1].现将AR的研究进展综述如下.     

冠心病患者阿司匹林抵抗的临床特征及与C反应蛋白、血栓素B2的关系

目的 探讨冠心病患者阿司匹林抵抗(AR)的临床特征及其与C反应蛋白(CRP)、血栓素B2(TXB2)的关系.方法 256例冠心病患者口服阿司匹林100 mg/d,7 d后测定血小板聚集率、CRP、TXB2;依据血小板聚集率测定结果将患者分为阿司匹林抵抗(AR)组、阿司匹林半抵抗(ASR)组和阿司匹林敏感(AS)组,比较三组间临床特征、CRP、TXB2的不同.结果 冠心病AR的发生率为5.86%,ASR发生率为24.22%;与AS组相比,AR组和ASR组患者的血小板(PLT)和血浆纤维蛋白原(Fg)水平升高(P<0.05),同时ASR组患者中女性患者比例明显升高(P<0.05),AR组或ASR组患者TXB2水平明显升高(P<0.05),而CRP在三组间无明显统计学差异.结论 冠心病患者存在AR现象,PLT和血浆Fg升高患者更易于发生AR,TXB:可用于检测AR现象.     

老年人尿11-脱氢血栓素B2和阿司匹林抵抗的相关性研究

目的研究老年人阿司匹林抵抗（aspirin resistance,AR）的发生情况及与尿11-脱氢血栓素B2（11—DH—TXB2）的相关性。方法入选300名汉族老年人作为研究对象,所有研究对象均长期服用阿司匹林（ASA）。检测其血小板聚集率,用酶联免疫吸附法（ELISA）测定尿11-DH—TXB2浓度,并分析其与血小板聚集率的相关性。结果阿司匹林敏感（aspirin sensitive,AS）者共102例,占34．0％;阿司匹林半抵抗（aspirin semi—resistance,ASR）者共113例,占37．7％;AR者共85例,占28．3％。尿11-DH—TXB2的浓度与二磷酸腺苷（ADP）及花生四烯酸（AA）诱导的血小板平均聚集率均呈明显的正相关（P〈0．01）。结论尿11-DH—TXB2的浓度反应体内血小板聚集程度,从而可能反映老年人是否存在AR。     

糖尿病对冠心病患者阿司匹林抵抗的影响

选择冠心病患者122例,按是否合并糖尿病分为两组,所有患者均服用阿司匹林100mg／d,服用时间32周。检测血小板聚集率（PAG）、血浆血栓素B2（TXB2）、尿TXB2、血脂、C反应蛋白（CRP）等指标。发现冠心病组阿司匹林抵抗（AR）发生率为16％（11／68）,冠心病合并糖尿病组AR发生率13％（13／54）,两组PAG、血TXB2、尿TXB2浓度比较无统计学差异,冠心病合并糖尿病组TG、LDL-C、LP（a）、CRP高于冠心病组（P〈0．05）。认为糖尿病与冠心病患者发生AR无关。     

阿司匹林抵抗相关研究进展

阿司匹林抵抗描述了导致阿司匹林在预防血栓并发症、引起出血时间延长、体外抑制血小板聚集以及抑制血小板血栓素形成等方面效力降低的多种不同现象。通过生化方法测定,我们将阿司匹林抵抗分为三种不同类型,此种分型有助于阐述阿司匹林抵抗的机制,包括药物剂量不足、血小板周转加快、药物依从性差、相关基因多态性以及血栓素非经血小板旁路途径形成等。     

阿司匹林抵抗及其发生机制(二)

3　ASA抵抗的发生机制ASA抵抗的发生机制可能与下列因素有关 :①ASA剂量不足 ;②可能和COX - 1有关 ;③可能和COX - 2有关 ;④可能和血小板膜糖蛋白Ⅱb/Ⅲa受体复合物的多态性有关。3.1　ASA剂量不足　尽管低剂量ASA能够完全抑制COX - 1,但是某些患者可能需要更高的剂量才能达到所需要的抗血小板效果。上个世纪 90年代早期 ,已在脑卒中患者中探讨过这个问题。Hel gason等[10 ] 研究表明 ,对低剂量ASA只有部分反应的 2 8例脑卒中患者 ,将其ASA剂量增加到130 0mg,其中 2 5例患者的血小板聚集反应则被完全抑制 ,表明ASA对血小板…     

阿司匹林抵抗及其发生机制(一)

阿司匹林(aspirin,Acetylsalicylic Acid,ASA)作为镇痛、抗炎和解热药物在临床应用已有100多年的历史.上个世纪50年代研究发现使用ASA可使出血时间延长,70年代动物实验研究开始阐明了ASA抗栓作用的机制.     

阿司匹林抵抗

自20世纪70年代起,阿司匹林作为抗血小板药物广泛用于心血管疾病的预防和治疗,大量循证医学证据证实心脑血管疾病高危患者应用阿司匹林,可使心脑血管事件如心肌梗死、脑卒中降低25%。但是,近年研究发现仍有部分服用阿司匹林的患者不能充分抑制血小板功能而致临床血栓事件的发生     

Variation in thromboxane B2 concentrations in serum and plasma in patients taking regular aspirin before and after clopidogrel therapy

Dual antiplatelet therapy with aspirin and a P2Y₁₂ antagonist is widely prescribed for the prevention of thrombotic events in patients with an acute coronary syndrome or undergoing percutaneous coronary intervention (PCI). It is recognised that there is inter-individual variation in the antiplatelet effects of both drugs. Recent data also suggest that P2Y₁₂ antagonists can affect the response to aspirin. A direct indicator of the effect of aspirin on platelets is their ability to generate thromboxane, which if measured as the difference between the level of thromboxane B₂ in serum and plasma ([TxB2]_S-P) avoids the confounding effect of endogenous TxB2 production from other cells. We therefore analysed [TxB2]_S-P as a measure of aspirin response in a group of 123 patients undergoing elective PCI before and after the introduction of clopidogrel. In a subgroup of 40 patients taking aspirin alone, we compared [TxB2]_S-P and VerifyNow Aspirin for the assessment of aspirin response. There was a wide variation in plasma and serum TxB2 concentrations both before and after clopidogrel therapy but only 3.5% of patients had residual serum concentration of TxB2 > 10?ng/ml. There was a strong correlation between the pre and post clopidogrel levels of TxB2 (r?≥?0.78; p?=?0.001) and no significant difference in [TxB2]_S-P. There was no correlation between the magnitude of response to clopidogrel response and the generation of thromboxane B2. Correlation between [TxB2]_S-P and VerifyNow Aspirin was poor. We conclude that the use of a P2Y₁₂ antagonist does not influence the effect of aspirin on the ability of platelets to generate thromboxane. Therefore, measurement of TxB2 levels in serum, after subtracting the contribution from plasma, provides a measure of the response to aspirin in patients taking dual antiplatelet therapy.     

Aspirin response: Differences in serum thromboxane B2 levels between clinical studies

Serum thromboxane B2 (TxB2) is a specific marker of platelet inhibition by aspirin. Yet, TxB2 levels differ by up to 10-fold between some aspirin-treated patient cohorts. This study aimed to identify factors responsible for differences in serum TxB2 between cohorts in the ADRIE study (n?=?657) and the BOSTON study (n?=?678) of aspirin-treated cardiovascular patients originally tested with different ELISA assays. TxB2 levels were assessed in representative subgroups of the two cohorts (34 samples in BOSTON and 39 in ADRIE) by both ELISAs, as well as liquid chromatography and tandem mass spectroscopy (MS). A multivariate analysis was performed on the whole cohort database to identify determinants of the difference of TxB2 levels between cohorts. There was no systematic bias between the original ELISA TxB2 values and the MS values and the median difference was small, 0.12?ng/ml, thus not explaining the difference between median TxB2 levels in the two study populations (7 and 0.6?ng/ml in the ADRIE and BOSTON studies, respectively). In the combined dataset of the ADRIE and BOSTON cohorts (n?=?1342), body mass index, age, gender, aspirin dose, time from aspirin intake to blood draw, NSAID intake, platelet count and C-reactive protein were significantly associated with TxB2 levels. After adjustment for patient characteristics, the difference between cohorts did not decrease. Unexplained differences in serum TxB2 levels in different populations of aspirin-treated cardiovascular patients suggest that further studies are needed to confirm the role of serum TxB2 level as a prognostic factor or rather as a marker of therapeutic observance.     

Prevalence of aspirin resistance in patients with type 2 diabetes

Abstract Aspirin resistance has been recognised to occur in patients with cardiovascular disease and is associated with poor clinical prognosis. The purpose of the present study was to evaluate the prevalence of aspirin resistance in 172 patients with diabetes mellitus type 2 (DM-2). Platelet function of 172 consecutive patients with type 2 diabetes on chronic aspirin therapy was evaluated. The effect of aspirin was assessed using the platelet function analyser (PFA-100) system, reporting platelet-dependent thrombus formation as the time required to close a small aperture in a biologically active membrane. Resistance to aspirin was defined as a normal collagen/epinephrine-induced closure time (82–165 s). Aspirin responders were defined when closure time was 300 s. Thirty-seven (21.5%) of the type 2 diabetic patients were found to be resistant to chronic aspirin therapy, 29 (16.9%) were semi-responders and 106 (61.6%) were responders. Univariate analysis revealed that aspirin non-responders were significantly younger (p<0.05) compared to aspirin responders. A significant number of type 2 diabetic patients are resistant to aspirin therapy. Aspirin resistance can be evaluated by point-of-care testing and should be recognised in diabetic patients that are treated for primary or secondary prevention.     

Determinants of aspirin resistance in patients with type 2 diabetes

BackgroundCardiovascular disease is a leading cause of mortality among patients with type 2 diabetes mellitus (T2DM). Numerous patients with T2DM show resistance to aspirin treatment, which may explain the higher rate of major adverse cardiovascular events observed compared with non-diabetes patients, and it has recently been shown that aspirin resistance is mainly related to accelerated platelet turnover with persistent high platelet reactivity (HPR) 24 h after last aspirin intake. The mechanism behind HPR is unknown. The aim of this study was to investigate the precise rate and mechanisms associated with HPR in a population of T2DM patients treated with aspirin.MethodsIncluded were 116 consecutive stable T2DM patients who had attended our hospital for their yearly check-up. HPR was assessed 24 h after aspirin intake using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum thromboxane B2 (TXB2) measurement. Its relationship with diabetes status, insulin resistance, inflammatory markers and coronary artery disease (CAD) severity, using calcium scores, were investigated.ResultsUsing LTA, HPR was found in 27 (23%) patients. There was no significant difference in mean age, gender ratio or cardiovascular risk factors in patients with or without HPR. HPR was significantly related to duration of diabetes and higher fasting glucose levels (but not consistently with HbA_1c), and strongly related to all markers of insulin resistance, especially waist circumference, HOMA-IR, QUICKI and leptin. There was no association between HPR and thrombopoietin or inflammatory markers (IL-6, IL-10, indoleamine 2,3-dioxygenase activity, TNF-α, C-reactive protein), whereas HPR was associated with more severe CAD. Similar results were found with TXB2.ConclusionOur results reveal that ‘aspirin resistance’ is frequently found in T2DM, and is strongly related to insulin resistance and severity of CAD, but weakly related to HbA_1c and not at all to inflammatory parameters. This may help to identify those T2DM patients who might benefit from alternative antiplatelet treatments such as twice-daily aspirin and thienopyridines.     

Clinical importance of aspirin and clopidogrel resistance

Aspirin and clopidogrel are important components of medical therapy for patients with acute coronary syndromes, for those who received coronary artery stents and in the secondary prevention of ischaemic stroke. Despite their use, a significant number of patients experience recurrent adverse ischaemic events. Interindividual variability of platelet aggregation in response to these antiplatelet agents may be an explanation for some of these recurrent events, and small trials have linked "aspirin and/or clopidogrel resistance", as measured by platelet function tests, to adverse events. We systematically reviewed all available evidence on the prevalence of aspirin/clopidogrel resistance, their possible risk factors and their association with clinical outcomes. We also identified articles showing possible treatments. After analyzing the data on different laboratory methods, we found that aspirin/clopidogrel resistance seems to be associated with poor clinical outcomes and there is currently no standardized or widely accepted definition of clopidogrel resistance. Therefore, we conclude that specific treatment recommendations are not established for patients who exhibit high platelet reactivity during aspirin/clopidogrel therapy or who have poor platelet inhibition by clopidogrel.     

阿司匹林抵抗的机制

近年来,阿司匹林抵抗现象越来越引起重视.研究人员已从多个方面对这种重要现象的机制进行了探索,包括患者依从性、实验室检测方法、阿司匹林剂量、遗传学、药物相互作用等；并提出了相应的管理方法,如提高患者依从性、避免药物相互作用、调整药物剂量、加用其他有潜在应用价值的抗血小板药等.文章对阿司匹林抵抗机制的研究进展进行了综述.     

Simvastatin administration reduces thromboxane production in subjects taking aspirin: links between aspirin resistance and thrombin generation

Background

Growing evidence indicates that statins may reduce thromboxane A₂ synthesis and thrombin generation. We investigated the relationships between thromboxane production, thrombin generation, and oxidative stress in patients receiving aspirin before and after statin administration.

Methods

An open-label study was conducted in 112 men, aged 54.4 ± 7.3 years, at an increased cardiovascular risk receiving aspirin (75 mg/d). Prior to and following a 3-month simvastatin treatment (40 mg/d), we evaluated circulating thromboxane B₂ (TXB₂), inflammatory markers, 8-isoprostane, and prothrombin fragment 1.2 (F1.2), a marker of thrombin generation, which was also measured in blood collected every 60 s at the site of standardized skin incisions.

Results

Subjects (n = 28) with pretreatment TXB₂ concentrations in the highest quartile (“aspirin-resistant patients”) were more frequently current smokers and had elevated C-reactive protein (CRP), interleukin-6, 8-isoprostane, shorter bleeding time, and increased F1.2 production in a model of microvascular injury, when compared with the 3 remaining quartiles (all, p < 0.001). Simvastatin decreased serum TXB₂ in the whole group (by 20%, p = 0.0008). Patients in the highest quartile of the baseline TXB₂ had still higher posttreatment TXB₂, CRP, interleukin-6, and F1.2 formation following injury (all, p < 0.001). Simvastatin-induced change in TXB₂ correlated with the magnitude of changes in maximum levels and the velocity of F1.2 formation (all p < 0.001) but not with changes in inflammatory markers or lipid profile.

Conclusions

The study shows that statins significantly reduce platelet TXA₂ formation in patients taking low-dose aspirin and this effect is associated with attenuated thrombin formation in response to vascular injury.     

阿司匹林抵抗的临床与实验研究进展

阿司匹林抵抗的可能原因包括低依从性、药物交叉反应、药物剂量不足、血小板周转加快、相关基因多态性以及血栓素非经血小板旁路途径形成等.现有的针对阿司匹林抵抗的实验室方法包括对TXA2及其代谢产物的检测和血小板功能的测定,临床上应采取措施减少阿司匹林抵抗以取得理想的预防和治疗效果.     

代谢综合征患者阿司匹林抵抗的临床研究

目的探讨代谢综合征患者阿司匹林抵抗的发生率和临床特征。方法对2005年5月至6月北京首钢社区人群中221例病情稳定的代谢综合征患者,口服阿司匹林200mg/d共10d后,应用血小板聚集仪测定花生四烯酸(AA)诱导的血小板聚集率。以0.5g/LAA诱导的血小板平均聚集率≥20%为阿司匹林抵抗。结果阿司匹林抵抗发生率为17.6%(39/221)。阿司匹林抵抗(AS)组患者的纤维蛋白原水平显著高于阿司匹林敏感(AR)组的患者[(2.6±0.4)g/L对(2.4±0.4)g/L,P=0.017)]。两组患者的血压、年龄、空腹血糖、血脂以及体重指数等差异均无统计学意义;性别、吸烟、既往心梗或脑梗病史的分布也无统计学意义。进一步根据患者性别进行分层分析发现,在男性患者中心梗病史是阿司匹林抵抗的预测因素(50%对14.5%,P=0.020),在女性患者中舒张压高于85mmHg(1mmHg=0.133kPa)是阿司匹林抵抗的预测因素(34.0%对15.5%,P=0.043)。结论研究人群中阿司匹林抵抗的发生率为17.6%,高纤维蛋白原是阿司匹林抵抗的危险因素,心梗病史和较高的舒张压可能分别是男性和女性阿司匹林抵抗的预测因素。