抗血小板药物“治疗无反应”的研究进展

doi:10.3969/j.issn.1673-8640.2015.12.022

摘要/Abstract

摘要：

近年来新型抗血小板药物陆续出现,阿司匹林与氯吡格雷双联抗血小板仍是目前预防支架内血栓形成及不良心血管事件发生最常用药物。接受标准双联抗血小板药物治疗有部分患者仍再次发生临床缺血事件,出现抗血小板药物“治疗无反应”现象引起了人们极大关注。关于这一现象研究很多,这些研究都有一定局限性,如不同实验室检测体外血小板功能方法不同、不同患者对抗血小板药物反应存在广泛个体差异以及其他疾病对抗血小板药物疗效影响等。文章主要从体外检测血小板功能方法、药物代谢基因多态性及影响抗血小板药物代谢相关临床疾病等方面总结目前可能得到的证据,来阐述影响残余血小板活性原因及其与血栓形成事件之间关系。

关键词: 抗血小板药物, 治疗无反应, 血小板活性, 基因多肽性

Abstract:

Despite the development of new antiplatelet agents,aspirin and clopidogrel dual antiplatelet therapy still has a major role in the prevention of stent thrombosis and ischemic events. However, a considerable number of patients in treatment with standard dual antiplatelet therapy continue to have cardiovascular events. This has been,in part,attributed to the fact that some patients may have poor antiplatelet effects. This phenomenon has caused considerable attention. Recently, a lot of researches on this phenomenon have appeared. However, these studies have some limitations, such as, the difference of platelet function tests, high inter-individual variability of antiplatelet agents and some other diseases affecting antiplatelet drug. In this review, we mainly discuss in vitro platelet function tests,genetic polymorphisms and some clinical disease interference with antiplatelet agents to elaborate the relationship between the reason of interference with antiplatelet agents and ischemic events.

Key words: Antiplatelet drug, Nonresponder, Platelet activity, Genetic polymorphism

中图分类号:

R446.11

崔婵娟, 乔蕊, 张捷. 抗血小板药物“治疗无反应”的研究进展[J]. 检验医学, 2015, 30(12): 1257-1262.

CUI Chanjuan, QIAO Rui, ZHANG Jie.. Research progress of antiplatelet drug "nonresponder"[J]. Laboratory Medicine, 2015, 30(12): 1257-1262.

图/表 4

图1 VASP试验特异检测P2Y12拮抗药物作用

表1 CYP2C19基因变异在不同种族中的差异[23] (%)

等位基因	高加索人	非洲裔美国人	亚洲人
^*2	28	21	50
^*3	<1	<1	18
^*17	33	29	6

图2 预测HTPR和MACE模型图[29]

图3 HTPR和年龄生存曲线[29]

参考文献 40

[1]	SAMARA WM,GURBEL PA.The role of platelet receptors and adhesion molecules in coronary artery disease[J]. Coron Artery Dis,2003,14(1): 65-79.
[2]	LEVINE GN,BATES ER,BLANKENSHIP JC,et al.2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions[J]. Catheter Cardiovasc Interv,2012,79(3): 453-495.
[3]	MAREE AO,FITZGERALD DJ.Variable platelet response to aspirin and clopidogrel in atherothrombotic disease[J]. Circulation,2007,115(16): 2196-2207.
[4]	SILLER-MATULA JM,SPIEL AO,LANG IM,et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel[J].Am Heart J,2009,157(1): 148.e1-148.e5.
[5]	TTH O,CALATZIS A,PENZ S,et al. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood[J]. Thromb Haemost,2006,96(6): 781-788.
[6]	SILLER-MATULA JM,DELLE-KARTH G,LANG IM,et al.Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study[J]. J Thromb Haemost,2012,10(4): 529-542.
[7]	RANUCCI M,BARYSHNIKOVA E,SORO G,et al.Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines[J]. Ann Thorac Surg,2011,91(1): 123-129.
[8]	SWEENY JM,GOROG DA,FUSTER V.Antiplatelet drug 'resistance'. Part 1: mechanisms and clinical measurements[J]. Nat Rev Cardiol,2009,6(4): 273-282.
[9]	GOROG DA,SWEENY JM,FUSTER V.Antiplatelet drug'resistance'. Part 2: laboratory resistance to antiplatelet drugs-fact or a.pngact[J]. Nat Rev Cardiol,2009,6(5): 365-373.
[10]	ATAULLAKHANOV FI,POHILKO AV,SINAURIDZE EI,et al.Calcium threshold in human plasma clotting kinetics[J]. Thromb Res,1994,75(4): 383-394.
[11]	BADR ESLAM R,LANG IM,KOPPENSTEINER R,et al.Residual platelet activation through protease-activated receptors(PAR)-1 and -4 in patients on P 2 Y 12 inhibitors[J]. Int J Cardiol,2013,168(1): 403-406.
[12]	GREMMEL T,PANZER S,STEINER S,et al.Response to antiplatelet therapy is independent of endogenous thrombin generation potential[J]. Thromb Res,2013,132(1): e24-e30.
[13]	CATTANEO M.Platelet P2 receptors: old and new targets for antithrombotic drugs[J]. Expert Rev Cardiovasc Ther,2007,5(1): 45-55.
[14]	SILLER-MATULA JM,PANZER S,Jilma B.Reproducibility and standardized reporting of the vasodilator-stimulated phosphoprotein phosphorylation assay[J]. Platelets,2008,19(7): 551-554.
[15]	FRERE C,CUISSET T,QUILICI J,et al.ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome[J]. Thromb Haemost,2007,98(4): 838-843.
[16]	SILLER-MATULA JM,CHRIST G,LANG IM,et al.Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator-stimulated phosphoprotein phosphorylation assay[J]. J Thromb Haemost,2010,8(2): 351-359.
[17]	FREYNHOFER MK,BRUNO V,WILLHEIM M,et al.Vasodilator-stimulated phosphoprotein-phosphorylation assay in patients on clopidogrel: does standardisation matter[J]. Thromb Haemost,2012,107(3): 538-544.
[18]	JEONG YH,BLIDEN KP,TANTRY US,et al.High on-treatment platelet reactivity assessed by various platelet function tests: is the consensus-defined cut-off of VASP-P platelet reactivity index too low[J]. J Thromb Haemost,2012,10(3): 487-489.
[19]	WRIGHT RS,ANDERSON JL,ADAMS CD,et al.2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines[J]. Circulation,2011,123(18): 2022-2060.
[20]	ANGIOLILLO DJ,FERNANDEZ-ORTIZ A,BERNARDO E,et al.Variability in individual responsiveness to clopidogrel: clinical implications,management,and future perspectives[J]. J Am Coll Cardiol,2007,49(14): 1505-1516.
[21]	SIMON T,VERSTUYFT C,MARY-KRAUSE M,et al.Genetic determinants of response to clopidogrel and cardiovascular events[J]. N Engl J Med,2009,360(4): 363-375.
[22]	OESTREICH JH,BEST LG,DOBESH PP.Prevalence of CYP2C19 variant alleles and pharmacodynamic variability of aspirin and clopidogrel in native Americans[J]. Am Heart J,2014,167(3): 413-418.
[23]	SHIN J.Clinical pharmacogenomics of warfarin and clopidogrel[J]. J Pharm Pract,2012,25(4): 428-438.
[24]	SORICH MJ,VITRY A,WARD MB,et al.Prasugrel vs. clopidogrel for cytochrome P450 2C19-genotyped subgroups: integration of the TRITON-TIMI 38 trial data[J]. J Thromb Haemost. 2010,8(8): 1678-1684.
[25]	BHATT DL,PAR G,EIKELBOOM JW,et al.The relationship between CYP2C19 ploymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study[J]. Eur Heart J,2012,33(17): 2143-2150.
[26]	ANGIOLILLO DJ.Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions[J]. Diabetes Care,2009,32(4): 531-540.
[27]	CAYLA G,HULOT JS,O'CONNOR SA,et al. Clinical,angiographic,and genetic factors associated with early coronary stent thrombosis[J]. JAMA,2011,306(16): 1765-1774.
[28]	NEUBAUER H,KAISER AF,ENDRES HG,et al.Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance-the BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy[J]. BMC Med,2011,9: 3.
[29]	SILLER-MATULA JM,LANG IM,NEUNTEUFL T,et al.Interplay between genetic and clinical variables affecting platelet reactivity and cardiac adverse events in patients undergoing percutaneous coronary intervention[J]. PLoS ONE,2014,9(7): e102701.
[30]	KAIKITA K,ONO T,IWASHITA S,et al.Impact of CYP2C19 polymorphism on platelet function tests and coagulation and inflammatory biomarkers in patients undergoing percutaneous coronary intervention[J]. J Atheroscler Thromb,2014,21(1): 64-76.
[31]	THOMSEN R,RASMUSSEN HB,LINNET K.In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors[J]. Drug Metab Dispos,2014,42(1):126-133.
[32]	KRISTENSEN KE,ZHU HJ,WANG X,et al.Clopidogrel bioactivation and risk of bleeding in patients cotreated with angiotensin-converting enzyme inhibitors after myocardial infarction: a proof-of-concept study[J]. Clin Pharmacol Ther,2014,96(6):713-722.
[33]	BONELLO L,TANTRY US,MARCUCCI R,et al.Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate[J]. J Am Coll Cardiol, 2010,56(12): 919-933.
[34]	ALEXOPOULOS D, XANTHOPOULOU I, PERPERIS A, et al.Factors affecting residual platelet aggregation in prasugrel treated patients[J]. Curr Pharm Des,2013,19(28): 5121-5126.
[35]	GREMMEL T,STEINER S,SEIDINGER D, et al.Obesity is associated with poor response to clopidogrel and an increased susceptibility to protease activated receptor-1 mediated platelet activation[J]. Transl Res,2013,161(5): 421-429.
[36]	DARLINGTON A,TELLO-MONTOLIU A,ROLLINI F,et al.Pharmacodynamic effects of standard dose prasugrel versus high dose clopidogrel in non-diabetic obese patients with coronary artery disease[J]. Thromb Haemost,2014,111(2): 258-265.
[37]	UENO M, FERREIRO JL, TOMASELLO SD, et al.Functional profile of the platelet P2Y12 receptor signalling pathway in patients with type 2 diabetes mellitus and coronary artery disease[J]. Thromb Haemost,2011,105(4): 730-732.
[38]	FERREIRO JL,UENO M,DESAI B,et al.Impact of adjunctive cilostazol therapy versus high maintenance dose of clopidogrel in suboptimal responders with diabetes mellitus[J]. Rev Esp Cardiol(Engl Ed),2012,65(1): 105-106.
[39]	JEONG YH,TANTRY US,BLIDEN KP,et al.Cilostazol to overcome high on-treatment platelet reactivity in Korean patients treated with clopidogrel and calcium-channel blocker[J]. Circ J,2011,75(11): 2534-2536.
[40]	MEGA JL,HOCHHOLZER W,FRELINGER AL 3rd,et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease[J]. JAMA,2011,306(20): 2221-2228.