1、UFH=unfractionated heparin.LMWH=low-molecular-weight heparinADP=adenosine diphosphate.TFPI=tissue factor pathway inhibitor Selwyn A.Am J Cardiol.2003;91:3H-11H.Coagulation cascadePlateletsLMWHThienopyridinesGP IIb/IIIa inhibitorsThrombolyticsLMWHUFHLMWHUFHDirect thrombininhibitorsTissue factorFactor
2、 XaProthrombinThrombinPlateletsA2 vWF ADPActivated plateletsFibrinogen cross-linkingPlatelet aggregationAspirinFibrinogenFibrinFibrindegradationCollagenLeukocytesTFPIAnti-thrombinAnti-thrombinThromboxanePlasminThrombusAlban.Eur J Clin Invest 2005 有效、安全、方便有效、安全、方便1930s1930s1940s1940s1980s1980s1990s19
3、90s2000s2000s普通肝素:多个作用靶点，注射VKAs:多个作用靶点，口服LMWHs:多个作用靶点，皮下注射直接凝血酶抑制剂:单个靶点，口服和注射间接Xa因子抑制剂:双靶点，注射直接Xa因子抑制剂单个靶点，口服现在现在DTIs,direct thrombin inhibitorsATIII+Xa+IIa(1:1 ratio)普通肝素普通肝素1930sATIII+Xa静脉间接静脉间接XaXa抑制剂抑制剂2002IIa口服直接口服直接凝血酶抑制剂凝血酶抑制剂2004ATIII+Xa+IIa(Xa IIa)低分子量肝素低分子量肝素1980sII,VII,IX,X(Protein C,S)华法
4、林华法林1940sXa口服直接口服直接XaXa抑制剂抑制剂2008IIa静脉直接静脉直接凝血酶抑制剂凝血酶抑制剂1990s希美加群希美加群达比加群达比加群口服直接口服直接Xa因子抑制剂因子抑制剂有利伐沙班有利伐沙班(Rivaroxaban）、）、阿哌沙班（阿哌沙班（Apixaban)、依杜沙班（依杜沙班（Edoxaban）、）、奥米沙班奥米沙班(Otamixaban)，间接间接Xa因子抑制剂为因子抑制剂为皮下注射的磺达肝葵皮下注射的磺达肝葵钠钠(Fondaparinux)和艾卓肝素和艾卓肝素(Idraparinux)比法卢定比法卢定Mackman N.NATURE.2008;451:914-9
5、18 Alban S.Current Pharmaceutical Design.2008;14:1152-1175Canales JF,et al.Am J Cardiovasc Drugs.2008;8(1):15-25GerotziafasGerotziafas GT,et al.J GT,et al.J ThrombThromb HaemostHaemost 2007;5:955962 2007;5:955962ACCP7.Chest.2004;126:188-203;WALENGA JM,et al.Turk J Haematol 2002;19(2):137-150;J EFFRE
6、Y I.WEITZ.The New England Journal of Medicine.1997;337:688-698;Alban S.Current Pharmaceutical Design.2008;14:1152-1175Alban S.Current Pharmaceutical Design.2008;14:1152-1175 依诺肝素（克赛）Clexane 那屈肝素（速避灵）Nadroparin 达肝素（法安明）Dalteparin主要主要LMWH化学结构化学结构相同的主链相同的主链不同的不同的末端侧链末端侧链1.European Pharmacopeia Commissi
7、on(March 1994)2.Knoll Pharma3.Hirsh J,et al.Chest 1998;114:489S-510SAnti-Xa activity was measured using an amidolytic assay(chromogenic substrate S-2222).Anti-IIa activity was measured using activated partial thromboplastin time4 Anti-XaAnti-Iia比率 (IU/mg 干质)(IU/mg 干质)Enoxaparin1依诺肝素102.824.94.1Nadro
8、parin1那屈肝素 103.629.93.5Reviparin2瑞肝素 127363.5Dalteparin1达肝素 167.264.22.4Certoparin1舍托肝素106.444.72.4Tinzaparin1亭扎肝素99.653.71.9UFH3普通 肝素1931931.0 R.J.Linhardt,D.Loganathan,A.Al-Hakim et al Oligosaccharide mapping of Low Molecular Weight Heparins:Structure and activity differences.J.Med.Chem;1990;33;16
9、39-1645J.Fareed,J.M.Walenga,D.Hoppensteadt et al.Biochemical and Pharmacologic Inequivalence of Low Molecular Weight Heparins.Ann N.Y.Acad.Sci.1989;556:333-353Nadroparin 那屈肝素Enoxaparin 依诺肝素Dalteparin达肝素Parnaparin帕肝素ardeparintinzaparinCY 222certoparinHeparin(PM)普通肝素%片段 7500 道尔顿%片段介于2500&7500道尔顿之间%片段
10、2500道尔顿依诺肝素（克赛）分子量分布集中1.Cohen M.Semin Thromb Hemost 1999;25(suppl 3):113-212.The FRAXIS study group.Eur Heart J 1999;20:1553-62 3.Klein W,et al.Circulation 1997;96:61-8 4.Antman EM,et al.Circulation 1999;100:1593-601 5.Cohen M,et al N Engl J Med 1997;337:447-52 LMWH,low-molecular-weight heparin;UFH,
11、unfractionated heparinFRAXIS2(nadroparin)n=3468FRIC3(dalteparin)n=1482TIMI 11B4(enoxaparin)n=3910ESSENCE5(enoxaparin)n=3171RRR-20%-15%-10%-5%0%5%10%15%20%3.9%0%-14.9%-16.2%LMWH superiorUFH superiorUA/NSTEMI 6-14天死亡、心梗、心绞痛复发联合终点天死亡、心梗、心绞痛复发联合终点Relative Risk Ratio(RRR)Significance NSP=0.03P=0.02NS普拉格雷
12、普拉格雷(60 mg LD,10 mg QD)氯吡格雷氯吡格雷(300 mg LD,75 mg QD)ASAN=13,608双盲双盲中位治疗时间中位治疗时间 14.5 个月个月ODonoghue ML et al.Lancet September 1,2009 DOI:10.1016/S0140-6736(09)61525-7LD：负荷剂量QD：维持剂量 00.511.522.5050100150200250300350400450患者百分比（%）HR 0.48 0.36-0.64 P0.00011 年:1.06 vs 2.15%HR 0.48 0.36-0.65,P0.00012.35%1.13%52%时间（天）氯吡格雷组普拉格雷组（N=6716）（N=6741）N Engl J Med2009;361:10451057.事件率（%）/年P值:NS
