阿司匹林抵抗的相关临床研究

目的:探讨我国患病人群中阿司匹林抵抗(aspirin resistance,AR)现象,比较不同AR实验检测法对阿司匹林疗效的判断及其临床应用价值。方法:对264例口服阿司匹林的患者(高血压、糖尿病等)分别进行光学法血小板聚集率(platelet aggregation test,PagT)、血栓弹力图(thrombelastography,TEG)、血和尿11-脱氢-血栓素B2(11-dehydro thromboxane B2,11-DH-TXB2)及P-选择蛋白表达检测,并对比分析患者的AR发生率、相关危险因素及AR与临床终点事件间的相关性。结果:口服阿司匹林患者采用各种方法检测到的AR发生率基本一致(P>0.05)。糖尿病患者AR和阿司匹林半抵抗(aspirin semi-resistance,ASR)的检出率有高于其他疾病组的趋势。低密度脂蛋白和空腹血糖的升高是AR的危险因素。几种检测方法的结果间有一定相关性(r为0.408～0.709,P<0.01)。以P-选择蛋白阳性为标准,TEG较其他检测方法有更高的灵敏度(89.29%)和特异度(92.31%),且与P-选择蛋白阳性间的一致性更高(K值为0.904,P<0.001)。结论:低密度脂蛋白升高和空腹血糖升高是AR发生的危险因素,TEG血小板图对AR检出的灵敏度较高,与P-选择蛋白检测结果间的一致性较高。     

原发性高血压患者阿司匹林抵抗及其与尿血栓素B2的关系

目的 初步探讨原发性高血压患者的阿司匹林抵抗(AR)情况及其与尿血栓素B2(TXB2)的关系.方法 EH患者147例和健康体检者33例服用阿司匹林100mg/d≥1周后,分别用花生四烯酸(AA)、二磷酸腺苷(ADP)作诱导剂检测血小板聚集率(PAG),并测定其尿TXB2的含量.AA诱导的血小板平均聚集率≥20%,同时ADP诱导的血小板平均聚集率≥70%者为AR;仅符合其中一项为阿司匹林半抵抗(ASR);均不符合者为阿司匹林敏感(AS).结果 原发性高血压组AR发生率为16.33%(24例),ASR发生率是8.84%(13例);AR、ASR患者尿TXB2浓度与AS患者比较,差异有统计学意义(F=54.43,P＜0.05);对照组AR、ASR发生率分别为3.03%(1例)、15.15%(5例);原发性高血压组AR发生率与对照组比较,差异有统计学意义(X2=4.07,P＜0.05);AA诱导的PAG(23.08±21.03%)显著高于对照组(11.88±8.02)% (t=5.03,P＜0.05).两组间ASR、AR ASR发生率差异无统计学意义(X2分别=1.19、0.73,P均＞0.05).180例入选者尿TXB2浓度与ADP诱导的PAG正相关(r=0.51,P＜0.05).结论 原发性高血压患者阿司匹林疗效降低,AR发生率升高;AR或ASR者尿TXB2浓度较高.     

阿司匹林抵抗的实验相关研究

目的 比较不同血小板功能检测方法对阿司匹林疗效判断及其临床应用价值.方法 采用血小板功能分析仪-100(platelet function analyzer,PFA-100)和光学法,应用不同的诱导剂(花生四烯酸、二磷腺苷酸、肾上腺素和胶原)测定血小板聚集率,分别对40例正常人、51例原发性高血压未服用阿司匹林患者及54例原发性高血压服用阿司匹林(100 mg/d)患者进行血小板功能测定,并以P-选择素水平的检测结果为对照,分析2种方法检测结果.结果 原发性高血压服用阿司匹林组(服药组)中4种诱导剂测得的光学法血小板聚集率较正常组和临床对照组均明显下降(P均＜0.05);服药组中PFA-100 CEPI测得的闭合时间(CT)值较正常组和临床对照组显著延长(P＜0.01).光学法血小板聚集检测的AR组及PFA-100测得的PFA-AR组中P-选择素的水平均显著增高.PFA-100对AR检出的敏感度较光学法血小板聚集高.PFA-100 CEPI检测盒与临床事件的一致性较光学法血小板聚集高.结论 光学法血小板聚集检测阿司匹林疗效,以AA作为诱导剂更敏感、特异;使用不同诱导剂进行监测有助于对更全面了解阿司匹林疗效;PFA-100较传统光学法血小板聚集有更好的敏感性,与临床事件的一致性高.     

血栓弹力图对急性脑梗死患者阿司匹林疗效监测价值

目的 探讨血栓弹力图检测对急性脑梗死患者阿司匹林疗效的监测作用.方法 对60例口服阿司匹林的急性脑梗死患者分别进行光学法血小板聚集率和血栓弹力图检测,比较2种检测方法的结果.结果 血小板聚集率和血栓弹力图检测血小板抵抗有较好的一致性(Kappa=0.76).结论 血栓弹力图检测对服用阿司匹林的急性脑梗死患者的药物疗效有较高临床价值,可用于评价抗血小板药物的临床疗效,指导临床治疗.     

奥扎格雷与阿司匹林对老年动脉粥样硬化患者抗血小板作用的比较

目的比较阿司匹林与奥扎格雷对老年动脉硬化高危患者血小板聚集率、血浆TXB2的影响及安全性判断。方法筛选81例在我科住院具有动脉硬化高危因素的患者随机分组,在常规治疗的基础上分别给与奥扎格雷、阿司匹林治疗和空白对照。治疗前后测定全血血小板最大聚集率和血浆血栓素B2水平,并观察血常规及生化指标。结果阿司匹林组血小板聚集率和血浆血栓素B2水平显著下降,奥扎格雷组仅血栓素B2下降具有统计学意义。二组均无严重不良反应,奥扎格雷组耐受性更好。结论阿司匹林的抗血小板作用显著又经济,奥扎格雷尚不适合预防用药。     

阿司匹林抵抗与尿11-脱氢-血栓素B2的检测及相关性研究

目的 探讨心脑血管病患者发生阿司匹林抵抗（aspirinresistance，AR）的影响因素以及AR与尿11-脱氢-血栓素B2（11-dehydro-Thromboxane，11-d-TXB2）的相关性。方法 220例心脑血管病患者服用阿司匹林（100mg／d）至少7d以上，用二磷酸腺苷和花生四烯酸作诱导剂测定血小板聚集功能，找出AR患者，测定11-d-TXB：的含量。结果 女性易发生AR，高血压患者发生AR几率高，AR者的11-d-TXB2含量同阿司匹林敏感者相比差异有统计学意义（P〈0．01）。结论 正确认识阿司匹林抵抗现象，对AR患者，可加大阿司匹林用量或换用其他抗血小板药物。     

服用小剂量阿司匹林对于冠心病患者的阿司匹林抵抗

目的探讨服用小剂量阿司匹林冠心病患者的阿司匹林抵抗（AR）现象及其相关因素。方法经冠脉造影确诊为冠心病患者137例，服用阿司匹林100mg／d≥1周后，分别用花生四烯酸（AA）、二磷酸腺苷（ADP）作诱导剂检测血小板聚集率。满足AA诱导的血小板平均聚集率≥20％、ADP诱导的血小板平均聚集率≥70％两项者为AR；仅满足其中一项为阿司匹林半抵抗（ASR）；均不满足者为阿司匹林敏感（脶）。结果137例患者中AR发生率为22．63％（31例），ASR发生率为17．52％（24例），AR＋ASR发生率为40．16％（55例）．AS发生率为59．85％（82例）。AR＋ASR组中的糖尿病、不稳定型心绞痛患者均较As组多（P〈0．05）；AR＋ASR组患者血浆总胆固醇浓度显著高于AS组（P〈0．05），血浆低密度脂蛋白-胆固醇浓度有高于AS组倾向（P〉0．053）。结论服用小剂量阿司匹林的冠心病患者AR＋ASR发生率为40．16％；AR或ASR者血浆胆固醇浓度较高；精尿病、不稳定型心绞痛患者AR或ASR发生率较高。     

老年心脑血管病患者阿司匹林抵抗及相关因素分析

目的了解老年心脑血管病患者阿司匹林抵抗（AR）的发生率,分析相关危险因素。方法选取老年缺血性心脑血管病患者150例,测定其血小板聚集率。将患者分为阿司匹林敏感（AS）组和非AS组。分别测定患者年龄、性别、红细胞计数、糖化血红蛋白等指标并比较组间差异。结果AR发生率为3．3％;阿司匹林半抵抗发生率为32．7％。非AS组吸烟百分比、红细胞计数及糖化血红蛋白水平明显高于AS组,差异有统计学意义（P〈0．05）。结论吸烟、红细胞计数及糖化血红蛋白水平升高是AR发生的危险因素。     

急性脑梗死患者阿司匹林抵抗危险因素分析

目的探讨急性脑梗死患者阿司匹林抵抗（AR）现象及其影响因素。方法收集330例急性脑梗死患者,根据血栓弹力图测定花生四烯酸（AA）诱导途径的血小板抑制率。血小板抑制率≤20％即判定为AR,抑制率在20％-50％之间则判定为阿司匹林半抵抗（ASR）,抑制率〉50％即为阿司匹林敏感（AS）。根据上述标准将患者进行分组,研究AR的发生率,并分析各组间各项临床特征的差异,采用Logistic回归分析影响AR与ASR的危险因素。结果330例急性脑梗死患者中AR发生率为33．9％,ASR发生率为19．7％。与As组相比,AR＋ASR组中高敏C反应蛋白（hs—CRP）水平明显升高（P〈0．05）。≥65岁患者中,高风险患者AR＋ASR发生率显著升高（P〈0．05）。Logistic回归分析表明血小板计数[OR=0．996,95％可信区间（CI）：0．991—0．999,P=0．041]和hs．CRP（OR=0．972,95％I：0．959—0．996,P=0．014）是发生AR与ASR的危险因素。结论急性脑梗死患者AR的发生率较可能与血小板数量和患者炎症状态有关。     

冠心病患者阿司匹林抵抗临床特征

目的:探讨冠心痛患者阿司匹林抵抗(AR)及阿司匹林半抵抗(ASR)的临床相关因素.方法:186例冠心病患者,光学法检测分别由二磷酸腺苷和花生四烯酸诱导的血小板聚集率.将患者分为AR或ASR组及阿司匹林敏感(AS)组.Logistic回归方法分析各临床因素与AR或ASR的相关性.结果:AR+ASR组与AS组中女性患者例数分别为28/58和39/128,糖尿病患者例数分别为23/58和26/128.低密度脂蛋白胆固醇(LDL-C)分别为(3.01 4±0.72)mmol/L和(2.7±0.65)mmol/L,均存在统计学差异(均P<0.05);AR+ASR组与AS组中高血压病怠者例数分别为23/58和34/128,吸烟患者例数分别为17/58和25/128,差异均无统计学意义(均P>0.05);总胆固醇、甘油三酯、高密度脂蛋白胆固醇、血小板计数及血红蛋白两组间比较差异无统计学意义(均P>0.05).Logistic回归分析显示高LDL-C血症及糖尿病是AR或ASR的易患因素.结论:AR或ASR在女性冠心病患者及合并糖尿病或高LDL-C的冠心病患者中易于发生,其中高LDL-C血症及糖尿病与AR或ASR相关性最强.     

不同剂量阿司匹林对血小板功能的作用及临床意义

不稳定性心绞痛 (UA)和急性心肌梗死 (AMI)发病 ,尤其是溶栓前尽速抑制血小板功能有利于病情的控制 ,为此探索国人使用血小板抑制剂的起效时间及合理的用药剂量有重要的临床意义。本文应用不同剂量阿司匹林观察其抑制血小板的起效时间并探讨其临床意义。材料与方法对象1999年 4月 - 2 0 0 0年 10月的 40例可疑冠心病(coronaryheartdisease,CHD)或可疑冠心病稳定性心绞痛和心律失常但无器质性心脏病的住院病人 ,年龄 18- 65岁 ,两周内未服用阿司匹林或影响血小板功能的药物 ,如噻氯匹定 ,潘生丁 ,消炎痛等抗凝剂及抗纤溶剂。凡有出血倾向…     

服用小剂量阿司匹林患者的阿司匹林抵抗

目的 探讨服用小剂量阿司匹林患者的阿司匹林抵抗（AR）现象及其影响因素.方法 入选328例病情稳定的心脑血管病、糖尿病等患者,每日服用阿司匹林100 mg,连服14 d后,分别用花生四烯酸（AA）、二磷酸腺苷（ADP）作诱导剂检测血小板聚集率.满足AA诱导的血小板平均聚集率≥20%、ADP诱导的血小板平均聚集率≥70%两项者为AR;仅满足其中一项为阿司匹林半抵抗（ASR）;均不满足者为阿司匹林敏感（AS）.用统计学方法分析各组间各项临床特征差异及影响AR与ASR的独立危险因素.结果 328例患者中AR发生率为4.9%,ASR发生率为27.4%.与AS相比,AR＋ASR中以女性、高龄、糖尿病及高血压病患者较多,吸烟者较少.Logistic回归分析表明,糖尿病[相对比值比（OR）=0.953,95%可信区间（CI）0.323～0.876,P=0.013]和高血压病（OR=0.610,95%CI 0.376～0.991,P=0.045）是发生AR与ASR的独立危险因素.不吸烟者发生AR与ASR的危险性升高（OR=2.231,95%CI 1.182～4.210,P=0.013）.结论 服用小剂量阿司匹林的患者中AR发生率为4.9%;发生AR与ASR可能与糖尿病、高血压等因素有关,不吸烟者发生AR与ASR的危险性升高.     

Persistent production of platelet thromboxane A2 in patients chronically treated with aspirin

BACKGROUND: Patients treated with aspirin may have a reduced sensitivity to its antiplatelet effect. The mechanism accounting for such a reduced sensitivity might involve an impaired interaction of aspirin with cyclooxygenase-1 (COX)-1. OBJECTIVE: We sought to investigate whether platelets from patients under chronic treatment with aspirin still produce TxA2 and whether there is any relationship between the eventual persistent TxA2 formation and platelet aggregation. Finally, whether platelet-derived TxA2 can be inhibited by in vitro addition of aspirin. METHODS: Collagen-induced platelet aggregation and thromboxane-A2 (TxA2) were measured in 196 patients treated with aspirin (100-330 mg day(-1)) because of previous vascular events or presence of risk factors of atherosclerosis. RESULTS: Collagen-induced TxA2 production of the entire cohort was 128.7 +/- 21.6 pg 10(-8) cells, and was significantly correlated with platelet aggregation (Spearman's correlation coefficient = 0.44; P < 0.0001). Patients in the highest quartile of TxA2 showed higher platelet response to collagen (P < 0.0001) when compared with those in the lowest quartile. In a subgroup of 96 patients, platelets were treated in vitro with a TxA2 receptor antagonist (13-azaprostanoic acid) or aspirin before stimulation with collagen. 13-APA acid significantly inhibited platelet aggregation. Aspirin reduced (-72.9%) TxA2 production in patients with TxA2 values above the median but it was ineffective in those with TxA2 values below the median. CONCLUSION: In some patients chronically treated with aspirin platelet production of TxA2 may persist and account for enhanced platelet aggregation. Incomplete inhibition of COX-1 seems to be implicated in persistent TxA2 production.     

Increased platelet sensitivity and thromboxane B2 formation in type-II hyperlipoproteinaemic patients

Platelet aggregation induced by collagen, ADP and epinephrine, was monitored in 150 type-II patients (115 type IIA and 35 type IIB) and compared with a reference group of normolipidaemic controls; in addition, malondialydehyde formation and thromboxane B2 were examined in a subsample of the type-IIA patients. Threshold aggregatory concentrations were significantly lower in the whole group of type-II patients for all three aggregating agents; no difference in terms of aggregatory response was detected between platelets from type-IIA and -IIB patients. Only 56% of type-II patients, however, exceeded the 95th percentile of the threshold aggregatory concentrations in controls. The formation of malondialdehyde in platelet-rich plasma stimulated with thrombin and collagen, was significantly higher in platelets from type-IIA patients. The production of thromboxane B2 by platelets, from endogenous arachidonic acid in type-IIA patients, was significantly higher and exceeded the highest level found in controls.     

莫诺苷对二磷酸腺苷诱导兔血小板聚集后血栓素B2的影响

目的观察莫诺苷对二磷酸腺苷(ADP)诱导兔血小板聚集后血栓素(TX)B2含量的影响。方法利用酶联免疫吸附剂测定法(ELISA)试剂盒,检测不同条件下ADP诱导血小板聚集后TXB2的含量。结果与对照组相比,莫诺苷能显著抑制由ADP诱导兔血小板聚集后TXB2的升高(P<0.001)。结论莫诺苷可以不同程度抑制ADP诱导兔血小板聚集后TXB2的生成。     

铝镁匹林对尿11-脱氢血栓素B2影响的长期观察

目的观察铝镁匹林抑制患者尿11-脱氢血栓素B₂(11-dH-TXB₂)的长期效果。方法103例患者给予铝镁匹林2片（含阿司匹林162 mg）口服。于用药前及用药6周、12周、24周后分别测定尿11-dH-TXB₂。结果尿11-dH-TXB₂治疗前及治疗后6周、12周、24周分别为（1840.41±1452.63） pg/ml、（820.01±610.55） pg/ml、（1011.19±1148.12） pg/ml、（1290.82±1425.51） pg/ml。12周时较6周时略有回升,但无显著性差异（P=0.1016）;24周较12周升高（P=0.0283）。结论铝镁匹林有明显的抗血小板聚集作用,但长期口服后作用可能有减弱的趋势。     

Aspirin withdrawal in patients treated with ticagrelor presenting with non‐ST elevation myocardial infarction

Essentials

• Strong P2Y₁₂ blockade may cause platelet inhibition that is only minimally enhanced by aspirin.
• We evaluated aspirin withdrawal on platelet reactivity in ticagrelor treated patients.
• Aspirin withdrawal resulted in increased platelet reactivity to arachidonic acid.
• Aspirin withdrawal caused little difference in adenosine diphosphate‐induced platelet aggregation.

Summary

Background

Recent studies have shown that the thromboxane A₂‐dependent pathway is dependent on the ADP–P2Y₁₂ pathway, and that strong P2Y₁₂ receptor blockade alone causes inhibition of platelet aggregation that is minimally enhanced by aspirin. Data from the PLATO trial suggested that, among ticagrelor‐treated patients, high‐dose versus low‐dose (< 100 mg day^?1) aspirin is associated with an increased risk fof ischemic events.

Objectives

To evaluate the impact of aspirin withdrawal on platelet reactivity in acute coronary syndrome (ACS) patients treated with a potent P2Y₁₂ blocker.

Patients/Methods

This was a current prospective, randomized, placebo‐controlled, double‐blind, cross‐over study. The study population comprised 22 consecutive ACS patients who underwent percutaneous coronary intervention and were treated with aspirin (100 mg day^?1) and ticagrelor. Thirty days post‐ACS, open‐label aspirin was stopped, and patients were randomized to either blinded aspirin or placebo for 2 weeks, with each patient crossing over to the other arm for an additional 2 weeks. Platelet reactivity to arachidonic acid and ADP determined with light‐transmission aggregometry (LTA) and VerifyNow was evaluated at baseline, and 2 weeks and 4 weeks later.

Results

Aspirin withdrawal resulted in an increase in arachidonic‐acid induced platelet reactivity as determined with both LTA (77.0% ± 11.3% versus 20.8% ± 4.4%) and VerifyNow (607.7 ± 10.6 aspirin reaction units [ARU] versus 408.5 ± 14.4 ARU). Platelet response to ADP, as determined with both LTA and VerifyNow, did not differ with either aspirin or placebo (32.9% ± 2.6% versus 35.8% ± 3.6%, and 33.5 ± 6.4 P2Y₁₂ reaction units (PRU) versus 29.6 ± 5.7 PRU, respectively).

Conclusions

Aspirin withdrawal early post‐ACS results in increased platelet reactivity in response to arachidonic acid, despite concomitant treatment with the potent P2Y₁₂ blocker ticagrelor.