1、血小板功能的检测方法血小板功能的检测方法 LTA：透光率集合度金标准 流式细胞仪 PFA100 血小板功能检测仪 Ultegra快速血小板功能测定(RPFA-ASA)Cone and Plate(let)分析仪(CPA)阿司匹林抵抗的定义阿司匹林抵抗的定义氯吡格雷抵抗的定义氯吡格雷抵抗的定义Serebruany V et al.J Am Coll Cardiol 2005;45:246-51 =-20服药前后血小板聚集率的改变服药前后血小板聚集率的改变(5M ADP)-10,011,20 31,40 51,60 71,80 91,100Gurbel PA et al.Circulation.2
2、003;107:2908-2913.近近25%的的AMI患者对氯吡格雷反应异常患者对氯吡格雷反应异常Matetzky S,et al.Circulation.2004;109(25):31713175.血小板对阿司匹林反应多样性血小板对阿司匹林反应多样性Gum PA,Kottke-Marchant K,Poggio ED,et al.Profile and prevalenceof aspirin resistance in patients with cardiovascular disease.Am JCardiol.2001;88(3):230235.Am J Cardiol.2001;
3、88(3):230235.近近50%的阿司匹林抵抗的患者同时存在氯吡格雷抵抗的阿司匹林抵抗的患者同时存在氯吡格雷抵抗J Am Coll Cardiol.2006;47(1):2733.血小板集聚功能的改变（血小板集聚功能的改变（5M ADP诱导的血小板聚集诱导的血小板聚集）=-20-10,011,20 31,40 51,60 71,80 91,100病例数病例数Adapted from:Serebrauny V et al.J Am Coll Cardiol 2005;45:246-51 低反应者是否有发生血低反应者是否有发生血栓事件的危险栓事件的危险?高反应者是否有出血的高反应者是否有出血的
4、风险风险?Matetzky S et al.Circulation 2004;109:3171-5在在AMI病人中，氯吡格雷抵抗增加再发血栓形成事件的危险性病人中，氯吡格雷抵抗增加再发血栓形成事件的危险性 1stN=152ndN=153rdN=154thN=15QuartilesC.6月月CVS 事件发生率事件发生率%Points1stN=152ndN=153rdN=154thN=154分位分位B.血小板聚集下降的程度血小板聚集下降的程度123456DaysClopidogrel Resistance1st Q2nd Q3rd Q4th QA.ADP-介导的血小板聚集介导的血小板聚集病人按氯吡
5、格雷治疗后的血小板抑制程度划分病人按氯吡格雷治疗后的血小板抑制程度划分为为4组组.比较比较4组病人的组病人的(a)与基线比较与基线比较ADP介导的血介导的血小板集聚的变化小板集聚的变化l率率;(b)第第6天与基线比较，血天与基线比较，血小板集聚率下降的程度小板集聚率下降的程度;(c)随访随访6月的主要心月的主要心血管不良事件发生率血管不良事件发生率.%of BaselineP=0.007对氯吡格雷反应差与支架内血栓发生有关对氯吡格雷反应差与支架内血栓发生有关Buonamici P,Marcucci R,Migliorini A,et al.Impact of plateletreactivit
6、y after clopidogrel administration on drug-eluting stentthrombosis.J Am Coll Cardiol.2007;49(24):23122317.Price MJ,Endemann S,Gollapudi RR,et al.Prognostic significance ofpost-clopidogrel platelet reactivity assessed by a point-of-care assay onthrombotic events after drug-eluting stent implantation.
7、Eur Heart J.2008;29(8):9921000.J Am Coll Cardiol.2007;49(24):23122317.血小板反应性与血小板反应性与DES植入后植入后MACE有关有关Buonamici P,Marcucci R,Migliorini A,et al.Impact of plateletreactivity after clopidogrel administration on drug-eluting stentthrombosis.J Am Coll Cardiol.2007;49(24):23122317.Price MJ,Endemann S,Goll
8、apudi RR,et al.Prognostic significance ofpost-clopidogrel platelet reactivity assessed by a point-of-care assay onthrombotic events after drug-eluting stent implantation.Eur Heart J.2008;29(8):9921000.Eur Heart J.2008;29(8):9921000.氯吡格雷低反应者易发亚急性支架内血氯吡格雷低反应者易发亚急性支架内血栓栓CREST研究研究Gurbel PA,Bliden KP,Sam
9、ara W,et al.Clopidogrel effect on plateletreactivity in patients with stent thrombosis:results of the CREST Study.J Am Coll Cardiol.2005;46(10):18271832.J Am Coll Cardiol.2005;46(10):18271832.抗血小板药物反应多样性的影响因素抗血小板药物反应多样性的影响因素 服药顺应性差服药顺应性差 吸收差吸收差 剂量不足剂量不足 吸烟吸烟 基因多态性基因多态性 血小板增多症血小板增多症 联合用药联合用药 合并疾病合并疾病
10、 严重冠状动脉粥样硬化性疾病严重冠状动脉粥样硬化性疾病阿司匹林抵抗的易发因素阿司匹林抵抗的易发因素Lee PY,Chen WH,Ng W,et al.Low-dose aspirin increases aspirinresistance in patients with coronary artery disease.Am J Med.2005;118(7):723727.Am J Med.2005;118(7):723727.服药依从性与血小板聚集率服药依从性与血小板聚集率Tantry US,Bliden KP,Gurbel PA.Overestimation of platelet as
11、pirinresistance detection by thrombelastograph platelet mapping and validationby conventional aggregometry using arachidonic acid stimulation.J Am Coll Cardiol.2005;46(9):17051709.J Am Coll Cardiol.2005;46(9):17051709.氯吡格雷生物利用度降低氯吡格雷生物利用度降低氯吡格雷反氯吡格雷反应变异应变异病人基线的个体差异病人基线的个体差异血小板生长周期加速血小板生长周期加速遗传变异遗传变异
12、CYP2C19基因多态性与氯吡格雷代谢相基因多态性与氯吡格雷代谢相关关*1*8 CYP2C19*2活性代谢产物浓度降低活性代谢产物浓度降低 CYP2C19*2携带者心血管死亡、心梗与卒携带者心血管死亡、心梗与卒中的风险增加中的风险增加N Engl J Med.2009;360(4):354362.CYP2C19基因多态性与心血管事件相关基因多态性与心血管事件相关N Engl J Med.2009;360(4):354362.氯吡格雷反应多样性氯吡格雷反应多样性-联合用药联合用药:PPIs Ho PM,Maddox TM,Wang L,et al.Risk of adverse outcomes
13、 associatedwith concomitant use of clopidogrel and proton pump inhibitorsfollowing acute coronary syndrome.JAMA.2009;301(9):937944.JAMA.2009;301(9):937944.PPIPPI对氯吡格雷抗血小板作用的影响对氯吡格雷抗血小板作用的影响PPI增加心血管事件风险增加心血管事件风险PPI不增加心血管事件风险不增加心血管事件风险-COGENT研研究究PPI显著降低显著降低GI事件的终点事件的终点如何应对血小板药物抵抗如何应对血小板药物抵抗 增加剂量增加剂量 联
14、合用药：阿司匹林联合用药：阿司匹林&双嘧达莫双嘧达莫 延长用药时间延长用药时间 P450同功酶诱导剂同功酶诱导剂 新型新型ADP受体拮抗剂受体拮抗剂Prasugrel增加阿司匹林剂量增加阿司匹林剂量Lee PY,Chen WH,Ng W,et al.Low-dose aspirin increases aspirinresistance in patients with coronary artery disease.Am J Med.2005;118(7):723727.Am J Med.2005;118(7):723727.增加氯吡格雷剂量增加氯吡格雷剂量OPTIMUS研究研究Circul
15、ation.2007;115(6):708716.氯吡格雷剂量氯吡格雷剂量血小板功能监测调整氯吡格雷负荷剂量血小板功能监测调整氯吡格雷负荷剂量Mean SDVASP after first LD,%VASP after adjustment,%Control68 11VASP-guided69 10 38 14*p0.4*0.001-Each additionnal bolus of 600 mg of clopidogrel decreased the number of patients with low response from 35 to 49%.-Despite 2400 mg o
16、f clopidogrel 11(14%)patients remained low-responders.血小板监测下的负荷剂量显著降低血小板监测下的负荷剂量显著降低PCI后后MACE MACE;n(%)Cardiovascular deathStent thrombosisRevascularizationOverall MACEControl(n=84)2(2)4(5)2(2)8(10)*VASP-guided(n=78)0000 p=0.059*p=0.007MACE:CV death,MI,revascularizationLog rank p=0.007新型抗血小板药物新型抗血小板
17、药物PrasugrelN Engl J Med.2007;357(20):20012015.新型抗血小板药物新型抗血小板药物Prasugrelstent thrombosis for all patients receiving at least one intracoronary stent.Lancet.2008;371(9621):13531363新型抗血小板药物新型抗血小板药物ticagrelor 不需代谢为活性形式不需代谢为活性形式 半衰期半衰期 78小时小时 可逆性可逆性ADP受体拮抗剂受体拮抗剂PLATO 研究设计研究设计Primary endpoint:CV death+MI+
18、Stroke Primary safety endpint:Total major bleeding612-month exposureClopidogrelIf pre-treated,no additional loading dose;if naive,standard 300 mg loading dose,then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)Ticagrelor180 mg loading dose,then90 mg bid maintenance;(additional 90 mg pre-PC
19、I)NSTE-ACS(moderate-to-high risk)STEMI(if primary PCI)Clopidogrel-treated or-naive;randomised within 24 hours of index event(N=18,624)PCI=percutaneous coronary intervention;ASA=acetylsalicylic acid;CV=cardiovascular;TIA=transient ischaemic attack PLATO 主要终点主要终点-KM曲线曲线No.at riskClopidogrelTicagrelor9
20、,2919,3338,5218,6288,3628,4608,124Days after randomisation6,7436,7435,0965,1614,0474,147060120180240300360121110987654321013Cumulative incidence(%)9.811.78,219HR 0.84(95%CI 0.770.92),p=0.0003ClopidogrelTicagrelorK-M=Kaplan-Meier;HR=hazard ratio;CI=confidence interval 8,6888,763010203086420Cumulative
21、 incidence(%)ClopidogrelTicagrelor4.775.43HR 0.88(95%CI 0.771.00),p=0.045No.at riskClopidogrelTicagrelor9,2919,3338,8758,9428,7638,827Days after randomisation319015021027033086420ClopidogrelTicagrelor5.286.608,6888,6738,2868,3976,3796,480Days after randomisation*HR 0.80(95%CI 0.700.91),p0.0018,4378,5436,9457,0284,7514,822Cumulative incidence(%)PLATO研究研究-主要终点主要终点*Excludes patients with any primary event during the first 30 days血小板功能监测血小板功能监测 治疗高血压时监测血压吗？治疗糖尿病时监测血糖吗？使用华法令时监测INR吗？使用抗血小板药物时，监测血小板功能吗？谢 谢！
