细胞色素P450基因变异与氯吡格雷抵抗及血管事件相关性

目的探讨细胞色素P450(cytochrome P450,CYP)相关基因多态性与氯吡格雷抵抗及随访期血管事件的相关性。方法连续纳入2014年6月~2015年1月接受氯吡格雷治疗的375例脑梗死患者。治疗前及治疗后7~10d检测血小板聚集率,采用质谱法检测8个CYP基因位点的多态性,多因子降维法分析基因-基因之间的交互作用,所有患者随访6个月。根据入组患者是否存在氯吡格雷抵抗分为:氯吡格雷抵抗组153例和氯吡格雷敏感组222例。结果氯吡格雷抵抗组CYP3A5(rs776746)GG+AG及CYP2C19*2(rs4244285)AG+AA基因型频率分布明显高于氯吡格雷敏感组,CYP3A5GG和CYP2C19*2AA基因型组合使氯吡格雷抵抗风险增加了2.23倍(OR=2.23,95%CI:1.08~5.87,P=0.025),且为原发终点发生的危险因素,CYP3A5GG和CYP2C19*2AA交互基因型者血小板聚集抑制率明显低于未携带者[(32.58±10.23)%vs(53.84±17.25)%,P=0.000]。结论CYP450相关基因变异及其交互作用与氯吡格雷抵抗和随访期血管事件发生相关。     

不同抗血小板药物联合治疗进展性脑梗死的比较

目的比较不同抗血小板药物(阿司匹林、氯吡格雷和奥扎格雷)联合治疗对进展性脑梗死患者的血小板活化水平和神经功能的影响。方法将97例急性进展性脑梗死患者随机分为A组(阿司匹林+氯吡格雷)、B组(阿司匹林+奥扎格雷)、C组(氯吡格雷+奥扎格雷),分别比较各组患者在治疗前、治疗3天后和治疗14天后血小板CD62P表达水平和临床神经功能缺损程度评分。结果三组患者联合抗血小板治疗14天后,与同组治疗前相比,血小板CD62P的表达水平和神经功能缺损程度评分均有明显下降(P<0.05),其中A组(阿司匹林+氯吡格雷)和C组(氯吡格雷+奥扎格雷)较B组(阿司匹林+奥扎格雷)下降更明显,差异有统计学意义(P<0.05)。结论对于进展性脑梗死患者尽早联合使用两种抗血小板药物治疗,可以取得较好的疗效,其中阿司匹林联合氯吡格雷和氯吡格雷联合奥扎格雷方案治疗效果更好。     

细胞色素P450酶2C19基因多态性与血小板高反应性相关性的研究

目的探讨急性冠状动脉综合征患者PCI术后细胞色素P450酶2C19(CYP2C19)基因多态性与血小板高反应性(HTPR)的相关性。方法选择急性冠状动脉综合征并接受PCI术的患者304例,根据二磷酸腺苷诱导的最大血小板聚集率是否大于50%分为HTPR组73例,非HTPR组231例。行CYP2C19*2、CYP2C19*3基因型检测,根据检测结果分为快代谢型、中间代谢型和慢代谢型。并利用最大血小板聚集率评价患者的血小板反应性。统计学分析CYP2C19基因多态性对血小板反应性的影响。结果 HTPR组快代谢型基因比例明显低于非HTPR组(28.8%vs 57.6%,P0.05),慢代谢型基因比例明显高于非HTPR组(13.7%vs 3.9%,P0.01)。慢代谢型患者最大血小板聚集率明显高于快代谢型和中间代谢型患者[(76.3±11.3)%vs(35.4±14.2)%和(45.1±15.8)%,P0.05]。结论 CYP2C19基因多态性对服用氯吡格雷患者的HTPR具有一定影响。慢代谢型患者最大血小板聚集率显著高于快代谢型和中间代谢型患者。     

奥美拉唑不同服药时间对氯吡格雷抗血小板效应的影响

目的:探讨分开氯吡格雷和奥美拉唑的服药时间对氯吡格雷抗血小板效应的影响。方法:入选急性冠状动脉综合征(ACS)患者56例,将其随机分为A组:单用氯吡格雷(21例);B组:氯吡格雷+奥美拉唑(20例);C组:氯吡格雷+奥美拉唑,间隔10～12h(15例)。采用PCR-RFLP检测患者的细胞色素P450(cytochromeP450,CYP)2C19*2和*3基因型,比浊法检测服药前及服药1d、5d的最大血小板聚集率(MPAR)。结果:3组CYP2C19*2和*3基因型的分布差异无统计学意义。服药1d和5d总的氯吡格雷抵抗发生率分别为42.86%和46.43%。服药1d后,A组MPAR与B、C组比较均差异有统计学意义(均P<0.05),而B组和C组差异无统计学意义。结论:联用奥美拉唑降低了氯吡格雷抗血小板效应,分开氯吡格雷和奥美拉唑服药时间不能减轻奥美拉唑对氯吡格雷的影响。     

氯吡格雷对大鼠肝微粒体细胞色素P450酶含量及CYP3A4活性的影响

目的探讨氯吡格雷对大鼠肝微粒体细胞色素P450(CYP450)含量及CYP3A4活性的影响。方法以生理盐水为对照,对照组大鼠灌胃给予1 ml生理盐水,氯吡格雷组大鼠每日灌胃给予6.75 mg/kg的氯吡格雷,连续7 d,然后测定大鼠肝微体中CYP450含量及CYP3A4活性。结果与对照组比较,氯吡格雷组的肝微粒体CYP450含量无变化(P0.05),CYP3A4活性明显降低(P0.01)。结论氯吡格雷对CYP450含量无影响,但对CYP3A4活性有抑制作用。     

他汀类药物对氯吡格雷抗血小板作用的影响

目的:观察他汀类药物对氯吡格雷抗血小板活性的影响,为他汀类联合氯吡格雷用药的合理性提供依据。方法:90例确诊为急性冠脉综合征的患者按随机数字表被分为氯吡格雷组、氯吡格雷+辛伐他汀组、氯吡格雷+普伐他汀组,各30例,三组患者均接受了常规药物治疗,并检测治疗前、治疗3d后血浆血小板α颗粒膜蛋白(CD62P)、溶酶体颗粒膜糖蛋白(CD63)及血小板最大聚集率(MPAR),并进行比较。结果:与治疗前比较,治疗后三组血浆CD62P、CD63水平及MPAR均有明显下降(P均0.01),且氯吡格雷组、氯吡格雷+辛伐他汀组和氯吡格雷+普伐他汀组间CD62P[(14.63±3.45)ng/ml比(14.14±4.32)ng/ml比(14.59±4.23)ng/ml]、CD63[(26.32±10.43)ng/ml比(27.04±10.75)ng/ml比(27.29±9.27)ng/ml]、MPAR[(28.62±17.68)%比(28.38±16.43)%比(29.13±14.23)%]差异均无统计学意义(P均0.05)。结论:短期、常规剂量的他汀类药物联合氯吡格雷治疗急性冠脉综合征不会影响氯吡格雷抗血小板功能。     

福建汉族脑梗死患者氯吡格雷抵抗的影响因素及与CYP2C19基因多态性的关系

目的探讨影响福建汉族脑梗死患者氯吡格雷抵抗的发生率、相关危险因素、与CYP2C19基因多态性的关系及其对白细胞介素6(IL-6)的影响。方法前瞻性纳入福建汉族脑梗死恢复期(≥3个月)患者102例。入院后给予氯吡格雷75 mg/d,于用药后第8天,采用血栓弹力图检测血小板聚集抑制率,其中≥40%为氯吡格雷敏感组,40%为氯吡格雷抵抗组。采用聚合酶链反应-限制性片段长度多态性方法检测CYP2C19*2和*3位点的基因型;酶联免疫吸附法检测治疗前后的血清IL-6水平。结果 102例患者中,氯吡格雷抵抗组27例,氯吡格雷抵抗发生率为26.5%。(1)氯吡格雷抵抗组低密度脂蛋白胆固醇(LDL-C)水平高于氯吡格雷敏感组[分别为(3.6±0.9)、(3.2±0.8)mmol/L,P0.05];而性别、高血压病、糖尿病、总胆固醇、三酰甘油及高密度脂蛋白胆固醇的差异均无统计学意义(P均0.05)。(2)两组患者的CYP2C19*2和CYP2C19*3位点等位基因频率和基因型总体分布不一致(P0.01)。氯吡格雷抵抗组的*1等位基因频率和*1/*1基因型频率明显低于氯吡格雷敏感组(分别为40.7%对比80.0%,18.5%对比61.3%,均P0.01),而*2等位基因频率和*2/*2基因型频率明显高于氯吡格雷敏感组(分别为53.7%对比18.7%,29.6%对比1.3%,P均0.01)。(3)治疗后氯吡格雷抵抗组IL-6浓度明显高于氯吡格雷敏感组[(18.4±1.8)ng/L对比(12.9±1.8)ng/L,P0.01]。与治疗前比较,氯吡格雷抵抗组血清IL-6水平下降(5.1±2.6)ng/L,低于氯吡格雷敏感组的(10.3±2.7)ng/L,P0.01。结论福建汉族脑梗死患者氯吡格雷抵抗发生率较高。氯吡格雷抵抗不仅与CYP2C19的突变型基因相关,而且与LDL-C增高有关。氯吡格雷抵抗削弱了药物的抗炎作用。     

细胞色素P2C19基因多态性对行介入治疗急性心肌梗死患者抗血小板药物的影响

目的检测行PCI的急性心肌梗死(AMI)患者细胞色素P2C19(CYP2C19)基因多态性,分析不同基因型患者抗血小板治疗的疗效。方法收集2016年6月～2018年6月郑州大学第二附属医院心内科接受PCI首次治疗的AMI患者247例,其中快代谢型(EM)56例,中间代谢型(IM)97例,慢代谢型(PM)94例,根据治疗方法分为氯吡格雷组172例和替格瑞洛组75例。采用流式细胞仪检测P选择素(CD62P)和血小板膜糖蛋白Ⅱb/Ⅲa复合物纤维蛋白原受体(PAC-1)表达水平,采用PCR检测2组患者CYP2C19基因型。结果 2组患者CYP2C19基因型分布和代谢类型分型比较,差异无统计学意义(P0.05)。治疗后,氯吡格雷组EM患者CD62P和PAC-1表达明显低于IM和PM患者(3.36±0.54 vs 4.52±1.07和4.47±1.25,2.24±0.81 vs 3.07±0.84和3.54±0.96,P0.01),IM与PM患者CD62P和PAC-1表达比较及替格瑞洛组EM、IM与PM患者CD62P和PAC-1表达比较,差异无统计学意义(P0.05);氯吡格雷组EM、IM和PM患者CD62P和PAC-1表达分别明显高于替格瑞洛组同代谢类型患者(P0.05,P0.01)。结论氯吡格雷和替格瑞洛均可抑制血小板活化标志物CD62P和PAC-1表达,替格瑞洛对血小板活化标志物的抑制作用强于氯吡格雷、且不受CYP2C19基因多态性的影响,在临床上,优先推荐阿司匹林联合替格瑞洛用于PCI后抗血小板治疗。     

CYP2C19基因多态性对老年人联用质子泵抑制剂与氯吡格雷的抑酸和抗血小板效果的影响

目的探讨细胞色素（cytochrome,CYP）2C19基因多态性对老年人联用质子泵抑制剂（proton pump inhibitator,PPI）与氯吡格雷的抑酸和抗血小板效果的影响。 方法选取2014年3月至2015年1月复旦大学附属华山医院老年病科收治的住院患者100例,均规律服用标准剂量PPI和（或）氯吡格雷。采用生物芯片法检测患者外周血CYP2C19基因型,根据基因型的不同代谢程度分组（强、中、弱代谢型组）,测定并比较不同代谢型组及各组内使用不同药物患者的胃液pH值、血小板抑制率（采用血栓弹力图检测）、PAG（M）（采用光学比浊法测定）。采用χ²检验分析CYP2C19基因型是否符合Hardy-Weinberg平衡;多组间比较应用单因素方差分析,进一步多重比较采用t检验;两组间的比较采用t检验。 结果强、中、弱代谢型组分别为42、46、12例;其中强代谢型组中单用PPI、单用氯吡格雷及PPI+氯吡格雷患者分别为16、14、12例,中代谢型组分别为22、10、14例,弱代谢型组分别为4、4、4例。CYP2C19等位基因的分布符合Hardy-Weinberg遗传平衡（χ²=0.49,P>0.05）。强、中、弱代谢型组间年龄、性别、血常规、肝肾功能、电解质、proBNP、血糖的差异均无统计学意义（均P>0.05）。强、中、弱代谢组中单用PPI患者血小板抑制率分别为（76.3±13.1）%、（55.9±19.1）%、（29.9%±6.1）%,差异有统计学意义（F=14.82,P<0.05）;单用氯吡格雷患者血小板抑制率分别为（76.3±13.1）%、（55.9±19.1）%、（29.9%±6.1）%,PAG（M）分别为（33.2±12.1）%、（35.2±13.8）%、（65.4±8.3）%,差异均有统计学意义（F=14.82、10.02,P<0.05或0.01）;PPI+氯吡格雷联用患者胃液pH值分别为3.66±0.7、4.5±0.5、5.0±0.7,血小板抑制率分别为（67.3±12.7）%、（40.6±25.8）%、（3.9±4.3）%,PAG（M）分别为（36.3±11.3）%、（56.2±24.0）%、（75.5%±12.3）%,差异均有统计学意义（F=9.33、15.46、7.08,P<0.05或0.01）。强代谢型组内,PPI+氯吡格雷与单用PPI患者胃液pH值的差异,以及PPI+氯吡格雷与单用氯吡格雷患者血小板抑制率及PAG（M）的差异均无统计学意义（t=-0.15、-1.70、0.67,均P>0.05）;中代谢型组内,PPI+氯吡格雷组与单用PPI患者胃液pH值的差异及PPI+氯吡格雷与单用氯吡格雷患者血小板抑制率的差异均无统计学意义（t=0.41、-1.05,P>0.05）,仅PPI+氯吡格雷与单用氯吡格雷患者PAG（M）的差异均有统计学意义[（56.2±24.0）%;（35.2±13.8）%;t=2.38,P<0.05]。弱代谢型组内,PPI+氯吡格雷与单用PPI患者胃液pH值的差异及PPI+氯吡格雷与单用氯吡格雷患者PAG（M）的差异无统计学意义（t=-0.13、1.18,均P>0.05）,仅PPI+氯吡格雷与单用氯吡格雷患者血小板抑制率的差异有统计学意义[（3.9±4.3）%,（29.9±6.1）%;t=-6.06,P<0.05]。应用经CYP450代谢药、CYP450酶抑制剂、不经CYP450酶代谢药患者胃液pH值分别为4.2±0.8、4.9±0.7、3.9±0.9,差异有统计学意义（F=3.12,P<0.05）。 结论CYP2C19基因多态性对老年人使用PPI的抑酸效果、氯吡格雷的抗血小板活性均有影响,PPI与氯吡格雷联合使用时可能相互减弱疗效,联用肝CYP450酶抑制剂会降低PPI的疗效。     

老年冠心病并发糖尿病患者PCI治疗后CYP2C19基因多态性与氯吡格雷抗血小板作用的关系

目的探讨老年冠状动脉粥样硬化性心脏病(冠心病)并发2型糖尿病(type 2 diabetes mellitus,T2DM)患者经皮冠状动脉介入(percutaneous coronary intervention,PCI)治疗后CYP2C19基因多态性与氯吡格雷抗血小板作用的关系。方法选取205例上海中医药大学附属普陀医院心内科2015年1月至2016年2月间住院行PCI治疗的患者,分为糖尿病组(116例)和对照组(89例)。检测CYP2C19基因型,记录患者服用氯吡格雷75 mg/d 7 d后血栓弹力图中二磷酸腺苷(adenosine diphosphate,ADP)抑制率指标。比较糖尿病组不同CYP2C19基因型患者氯吡格雷血小板抑制率的差异。记录应用氯吡格雷进行血小板预防治疗6个月后主要不良心血管事件(major adverse cardiovascular event,MACE)的发生率。结果 CYP2C19基因型检测结果显示,糖尿病组快代谢型36例(31.03%),中间代谢型58例(50.00%),慢代谢型22例(18.97%);对照组快代谢型50例(56.18%),中间代谢型31例(34.83%),慢代谢型例8例(8.99%)。糖尿病组患者3组基因型分布比较,差异有统计学意义(P0.05)。糖尿病组弱代谢型(中间代谢型+慢代谢型)氯吡格雷抵抗(clopidogrel resistance,CR)发生率明显高于对照组,差异有统计学意义(P0.05)。糖尿病组不同CYP2C19基因型患者血小板抑制水平比较,差异有统计学意义(P0.05)。PCI治疗后应用氯吡格雷进行血小板预防治疗6个月期间,糖尿病组与对照组之间MACE(不稳定心绞痛、支架内再狭窄)发生率比较,差异有统计学意义(P0.05)。进一步分析糖尿病组不同CYP2C19基因型患者,中间及慢代谢型患者MACE发生率明显高于快代谢型患者,差异有统计学意义(P0.05)。结论对于服用氯吡格雷抗血小板治疗的老年冠心病并发糖尿病PCI治疗后患者,通过检测CYP2C19基因多态性预测CR,对预防MACE的发生有一定帮助。     

替格瑞洛与氯吡格雷在ACS并发T2DM行PCI患者中对血小板聚集功能影响的比较

目的 观察急性冠脉综合征（ACS）并发2型糖尿病（T2DM）行经皮腔内冠状动脉介入（PCI）治疗患者中替格瑞洛与氯吡格雷对血小板聚集功能影响的比较。 方法 回顾性的收集2013年3月~2015年3月我院ACS并发T2DM行PCI患者175例,按使用的抗血小板药物分为两组:替格瑞洛组（n=22）和氯吡格雷组（n=153）,采用光比浊法分析血小板聚集功能,比较两者血小板聚集功能的差异。 结果 花生四烯酸（AA）诱导的血小板聚集率:氯吡格雷组为（32±20）%,替格瑞洛组为（26±17）%,两组差异无显著性;二磷酸腺苷（ADP）诱导的血小板聚集率:氯吡格雷组为（51±18）%,替格瑞洛组（40±18）%,两组有显著性差异（P=0.01）。 结论 对于ACS并发T2DM行PCI患者,替格瑞洛较氯吡格雷显著减低ADP诱导的血小板聚集率,不影响AA诱导的血小板聚集率。     

The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease

Peripheral arterial disease (PAD) is associated with platelet hyperactivity. Aspirin and clopidogrel, two platelet inhibitors, act by different mechanisms. Aspirin inhibits thromboxane A2 synthesis and clopidogrel acts on the P2Y12 platelet ADP receptor. We evaluated the effect of clopidogrel (75 mg/day), aspirin (75 mg/day) and then both drugs on several platelet function indices in patients with PAD (n = 20). There was a significant (P = 0.0001) decrease in ADP-induced aggregation, after clopidogrel but not after taking aspirin. Clopidogrel plus aspirin significantly decreased spontaneous platelet aggregation (SPA) (P = 0.01 to P = 0.002) but SPA was not significantly altered by either aspirin or clopidogrel monotherapy. Similarly, monotherapy did not inhibit serotonin (5HT)-induced aggregation but there was a sigificant inhibition (P = 0.03 to P < 0.02) after combination therapy. ADP (0.8 microM)-induced platelet shape change (PSC) was significantly inhibited by clopidogrel (P = 0.004) or aspirin (P = 0.01). This was also true for 5HT-induced PSC (clopidogrel, P = 0.01; aspirin, P = 0.03). Soluble P-selectin decreased significantly (from 32 +/- 24 to 25 +/- 17 ng/ml, P = 0.04) with combination therapy. Plasma platelet-derived growth factor and intraplatelet 5HT levels were not altered by combination therapy. In PAD, clopidogrel is a more potent inhibitor of ADP-induced platelet activation than aspirin; combination therapy is more effective than clopidogrel or aspirin monotherapy. These potentially clinically relevant findings should be evaluated in appropriately designed trials.     

2型糖尿病合并冠心病患者血小板表面CD62P和CD40L的表达水平

目的 探讨2型糖尿病合并冠心病患者血小板表面CD62P和CD40L的表达水平及其和血清高敏C反应蛋白的关系.方法 选择单纯冠心病患者34例、单纯2型糖尿病患者33例、2型糖尿病合并冠心病患者30例及对照者30例,采用流式细胞术分别检测血小板表面CD62P和CD40L的表达水平,并与血清高敏C反应蛋白作相关分析.结果 2型糖尿病合并冠心病组血小板CD62P、CD40L和高敏C反应蛋白水平较对照组、单纯冠心病组及单纯2型糖尿病组显著升高(P<0.01),血小板CD62P和CD40L与血清高敏C反应蛋白水平呈正相关(r分别为0.343和0.495,P均<0.05).结论 2型糖尿病合并冠心病患者的血小板表面CD62P和CD40L表达水平明显升高,并与血清高敏C反应蛋白明显正相关.血小板表面CD62P和CD40L的表达水平可能是预示糖尿病患者合并冠状动脉粥样硬化的重要指标.     

The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel

Recently we showed that the P2Y₁ receptor coupled to calcium mobilization is necessary to initiate ADP-induced human platelet aggregation. Since the thienopyridine compound clopidogrel specifically inhibits ADP-induced platelet aggregation, it was of interest to determine whether the P2Y₁ receptor was the target of this drug. Therefore we studied the effects of clopidogrel and of the two specific P2Y₁ antagonists A2P5P and A3P5P on ADP-induced platelet events in rats. Although clopidogrel treatment (50 mg/kg) greatly reduced platelet aggregation in response to ADP as compared to untreated platelets, some residual aggregation was still detectable. In contrast, A2P5P and A3P5P totally abolished ADP-induced shape change and aggregation in platelets from both control and clopidogrel-treated rats. A2P5P and A3P5P (100 μM ) totally inhibited the [Ca²⁺]_i rise induced by ADP (0.1 μM ) in control and clopidogrel-treated platelets, whereas clopidogrel treatment had no effect. Conversely, the inhibition of adenylyl cyclase induced by ADP (5 μM ) was completely blocked by clopidogrel but not modified by A2P5P or A3P5P (100 μM ). A3P5P (1 m M ) reduced the number of [³³P]2MeSADP binding sites on control rat platelets from 907 ± 50 to 611 ± 25 per platelet. After clopidogrel treatment, binding of [³³P]2MeSADP decreased to 505 ± 68 sites per platelet and further decreased to 55 ± 12 sites in the presence of A3P5P (1 m M ). In summary, these results demonstrate that the platelet P2Y₁ receptor responsible for the initiation of aggregation in response to ADP is not the target of clopidogrel. Platelets may express another, as yet unidentified, P2Y receptor, specifically coupled to the inhibition of adenylyl cyclase and necessary to induce full platelet aggregation, which could be the target of this drug.     

阿托伐他汀对不稳定型心绞痛病人血管内皮功能及血小板活化的影响

目的探讨阿托伐他汀对不稳定型心绞痛病人血管内皮功能及血小板活化的影响。方法 68例不稳定型心绞痛病人随机分成常规组(34例)和阿托伐他汀组(34例)。所有病人分别于入院时及用药4周后取血,行血清一氧化氮(NO)、血浆内皮素-1(ET-1)及血小板胞质内α-颗粒膜糖蛋白(CD62p)测定。另选本院同期健康体检者30名作为对照组,要求采血前两周内未服用任何药物。结果不稳定型心绞痛病人血NO水平显著低于对照组(P<0.01),ET-1、CD62p水平明显高于对照组(P<0.01)。治疗4周后两组病人血清NO水平显著升高,血浆ET-1、血小板CD62水平明显降低(P<0.01),且治疗后两组之间有统计学意义(P<0.01),但治疗4周后两组患者血NO水平仍低于对照组(P<0.01),ET-1、CD62p水平仍高于对照组(P<0.01)。结论阿托伐他汀有改善不稳定型心绞痛病人内皮功能,抑制血小板活性作用,阿托伐他汀10mg/d治疗4周后不稳定型心绞痛病人仍然存在内皮功能障碍及血小板活化的问题。     

Relationship between plasma inflammatory markers and platelet aggregation in patients with clopidogrel resistance after angioplasty

We evaluated the relationship between plasma inflammation markers and clopidogrel resistance in patients after stent implantation. The plasma levels of C-reactive protein (CRP), P-selectin, platelet soluble CD40 ligand (sCD40L), interleukin 6 (IL-6) and platelet aggregation were measured in 352 patients undergoing percutaneous coronary intervention (PCI) at baseline and after 6 months. The plasma levels of CRP, P-selectin, sCD40L, IL-6 was higher in 65 (18.5%) patients with clopidogrel resistance than in those with normal responsiveness at 6 months after PCI. There was a significant positive correlation between soluble CD40L levels and platelet aggregation (r = .28, P < .05). Diabetes (DM) and sCD40L level were independent predictors for unresponsiveness after stent implantation according to stepwise multivariate analyses. The hazard ratio (HR) for sCD40L level was 3.02 (95% CI = 1.28 to 3.25; P = .036) and for DM 2.53 (95% CI = 1.28 to 6.55, P = .03). We conclude that sCD40L and DM may influence clopidogrel resistance.     

Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome

Genetic polymorphisms of cytochrome P450 (CYP) isoforms may promote variability in platelet response to clopidogrel. This study was conducted to analyze, in 603 patients with non-ST elevation acute coronary syndromes, the effect of CYP3A4, CYP3A5, and CYP2C19 gene polymorphisms on clopidogrel response and post-treatment platelet reactivity assessed by adenosine diphosphate (ADP)-induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression. The CYP2C19*2 polymorphism was significantly associated with ADP-induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression in recessive (p <0.01, p <0.007, and p <0.06, respectively) and codominant (p <0.08, p <0.0001, and p <0.009, respectively) models, but the CYP3A4*1B and CYP3A5*3 polymorphisms were not. The CYP2C19*2 allele carriers exhibited the highest platelet index levels in multivariate analysis (p = 0.03). After covariate adjustment, the CYP2C19*2 allele was more frequent in clopidogrel nonresponders, defined by persistent high post-treatment platelet reactivity (ADP-induced platelet aggregation >70%; p = 0.03). In conclusion, the present data suggest that the CYPC19*2 allele influences post-treatment platelet reactivity and clopidogrel response in patients with non-ST elevation acute coronary syndromes.     

阿司匹林或氯吡格雷作用下血小板不同活化途径的反应特点

目的探讨阿司匹林和氯吡格雷抑制血小板环氧酶(COX)-1途径和P2Y12受体活化的特点及两途径之间的交互关系。方法 20例健康男性志愿者按随机数余数分组法平均分为两组,分别服用阿司匹林(100 mg/d)和氯吡格雷(75 mg/d)连续7 d。并在服药和停药后第1、3、5、7天分别应用血栓弹力图、血小板功能分析仪和流式细胞仪观察血小板的抑制情况。结果服药后,氯吡格雷组的胶原-肾上腺素激活的闭孔时间(CEPI-CT)和胶原-腺苷二磷酸闭孔时间(CADP-CT)的变化差异均有统计学意义(F=27.2,P<0.01,F=25.3,P<0.05),阿司匹林组CEPI-CT迅速增至检测上限300 s,差异有统计学意义(F=36.7,P<0.01),而CADP-CT变化差异无统计学意义(F=2.12,P=0.13)。服药后阿司匹林组血小板COX-1途径抑制率增高至91.7%±0.9%(F=35.1,P<0.01),氯吡格雷组P2Y12受体抑制率由47.8%±3.1%增高至81.3%±3.8%(F=24.8,P<0.01),COX-1未受到有效抑制(F=1.85,P=0.11)。服药后两组CD62p表达降低50%(氯吡格雷组:F=28.7,P<0.01;阿司匹林组:F=20.7,P=0.02)。结论花生四烯酸诱导的COX-1途径活化与P2Y12受体活化可能存在交互作用,床旁即时检验有助于快速了解血小板功能状态,为监测有效的联合用药提供依据。     

Effectiveness of reloading to overcome clopidogrel nonresponsiveness in patients with acute myocardial infarction

Whether increasing doses of clopidogrel can overcome nonresponsiveness was evaluated. Clopidogrel nonresponsiveness was found in up to 25% of treated patients and was associated with worse prognosis in patients with acute coronary syndrome and patients undergoing coronary intervention. Adenosine diphosphate (ADP)-induced platelet aggregation was prospectively determined on day 4 of acute myocardial infarction in 200 consecutive patients, who received clopidogrel 300 mg as a loading dose and 75 mg/day thereafter. Thirty patients (15%) had ADP-induced platelet aggregation >or=80% using light transmittance aggregometry and were considered clopidogrel nonresponders. Nonresponders were reloaded with clopidogrel 600 mg, followed by 150 mg/day for 4 weeks. A 75-mg/day dose was resumed thereafter. ADP-induced platelet aggregation was reassessed 4 hours after reloading and biweekly for 10 weeks. Flow cytometry was used to determine platelet P-selectin expression and fibrinogen binding before and 4 hours after reloading. ADP-induced platelet aggregation significantly decreased 4 hours after reloading (from 83 +/- 6% to 56 +/- 14%; p <0.01). The decrease in platelet aggregation was maintained throughout the 4-week doubled maintenance dose. After resuming a maintenance dose of 75 mg/day, ADP-induced platelet aggregation returned to 66 +/- 12% (p <0.001), and 5 patients (17%) had ADP-induced platelet aggregation >or=80%. Flow cytometry showed a significant decrease in P-selectin expression (from 37 +/- 16% to 26 +/- 13%; p <0.01) and fibrinogen binding (from 84 +/- 7% to 70 +/- 13%; p <0.01) in ADP-stimulated platelets 4 hours after reloading. In conclusion, clopidogrel reloading and increased maintenance dose may overcome clopidogrel nonresponsiveness in patients with acute myocardial infarction.     

通心络对急性冠状动脉综合征患者介入术后血小板活化及血管内皮功能的影响

目的评价通心络胶囊对急性冠状动脉综合征(ACS)介入治疗术后血小板活化状态及血管内皮功能的影响。方法90例ACS患者(ACS组)随机分为通心络胶囊治疗组(45例)和常规治疗组(45例),另选健康对照组45例,分别检测血小板表面活性标记蛋白CD62P、CD63和膜糖蛋白(GP)Ⅱb/Ⅲa,测定血浆血管性假血友病因子(vWF),并测量内皮依赖性血管舒张功能(FMD)。服用通心络胶囊治疗8周后复查上述指标并进行治疗前后比较及两组间比较。结果与健康对照组比较,ACS组患者血小板活化指标CD62P、CD63及GPⅡb/Ⅲa受体复合物显著升高(P<0.01),vWF显著升高(P<0.01),FMD显著降低(P<0.01)。冠状动脉介入术后vWF升高(P<0.05),FMD降低(P<0.05)。与常规治疗组比较,通心络胶囊治疗组更明显降低CD62P、CD63、vWF(P<0.05)及GPⅡb/Ⅲa复合物(P<0.01),增加FMD的水平(P<0.05)。结论通心络胶囊可用于冠状动脉介入术前后预防和治疗冠状动脉内血栓及保护血管内皮功能。