血栓形成机制与抗栓药物展望课件

血栓形成机制与抗栓药物展望

首都医科大学附属北京同仁医院史旭波FibrinPlateletsRBCs血栓的构成

RBCs,redbloodcells.血栓是机体维护血管壁结构完整的一种防护性反应正常内皮细胞有强烈抑血作用典型血管的剪切率血管类型剪切率(s-1)静脉20-200大动脉300-800小动脉500-1,600狭窄冠状动脉800-10,000动脉血栓形成高流速、高度依赖血小板动脉

TMPGI2预防和治疗动脉系统血栓抗血小板+抗凝治疗静脉血栓形成

低流速对血小板依赖程度很低静脉

TMPGI2预防和治疗静脉系统血栓抗凝治疗为主

血栓的类型动脉系统血栓形成高度依赖血小板抗血小板+抗凝治疗心腔内血栓形成对血小板依赖介入动静脉之间高危患者抗凝治疗为主，低危患者抗血小板治疗静脉系统血栓形成对血小板依赖较低抗凝治疗为主阿司匹林的抗血小板作用胶原

5-羟色氨

ADP凝血酶

TXA2刺激传递系统肾上腺素

cAMPCa++释放反应GPIIbGPIIIaCa++GPIIIaGPIIb纤维蛋白原聚集Aspirin

ACS患者阿司匹林的适宜剂量AntithromboticTrialists’Collaboration.BMJ.2002;324:71-86.00.51.01.52.0500–1500mg 34 19160–325mg 19 2675–150mg 12 32<75mg 3 13Anyaspirin 65 23AntiplateletBetterAntiplateletWorseAspirinDose #TrialsOR*(%)*Oddsreduction.TreatmenteffectP<0.0001.OddsRatio

药代动力学肠道吸收，肝脏代谢，2.2%~2.4%尿中排泄半减期为7.2~7.5小时75mg/d,

4–5天;300mg/d,4-6h;600mg/d,2h停药后作用可延续到7~10到稳定天，洗脱期长（氯吡格雷）血小板GPⅡb/Ⅲa拮抗剂作用机制

胶原

5-羟色氨

ADP凝血酶

TXA2刺激传递系统肾上腺素

cAMPCa++释放反应GPIIbGPIIIaCa++GPIIIaGPIIb纤维蛋白原聚集X西洛他唑潘生丁作用机制

胶原

5-羟色氨

ADP凝血酶

TXA2刺激传递系统肾上腺素

cAMPCa++释放反应GPIIbGPIIIaCa++GPIIIaGPIIb纤维蛋白原聚集X奥扎格雷钠的抗血小板作用胶原

5-羟色氨

ADP凝血酶

TXA2刺激传递系统肾上腺素

cAMPCa++释放反应GPIIbGPIIIaCa++GPIIIaGPIIb纤维蛋白原聚集奥扎格雷钠安步乐克作用机制

胶原

5-羟色氨

ADP凝血酶

TXA2刺激传递系统肾上腺素

cAMPCa++释放反应GPIIbGPIIIaCa++GPIIIaGPIIb纤维蛋白原聚集XPrasugrel抑制P2Y12药代动力学迅速起效（≤

2h）不可逆的结合与氯吡格雷激活的代谢途径不同比氯吡格雷更有效的抑制ADP引起的血小板激活Primaryendpoint:CVdeath,MIorstroke005101560120180240300360DaysafterrandomizationK-Mestimatedrate(%peryear)HR:0.84(95%CI=0.75–0.94),p=0.00259.0210.65ClopidogrelTicagrelorNo.atriskClopidogrelTicagrelor6,6766,7326,1296,2366,0346,1345,8814,8154,8893,6803,7352,9653,0485,972K-M=Kaplan-Meier;HR=hazardratio;CI=confidenceintervalTicagrelorClopidogrelNSNSNS0K-Mestimatedrate(%peryear)PLATOmajorbleeding12345678910121113TIMImajorbleeding11.511.68.08.02.93.2GUSTOseverebleeding*4.74.12.82.31.91.7Non-CABGandCABG-relatedmajorbleedingNon-CABGCABG*Preliminary–fromeCRF凝血酶受体拮抗剂TRASCH530348第一种此类药口服，长效阻断血小板PAR–1受体不干扰纤维蛋白形成对出血时间或PT/aPTT无影响抗血小板药物血栓素A2抑制剂阿司匹林(ASA)ADP-受体拮抗剂氯吡格雷噻氯匹啶糖蛋白(GP)IIb/IIIa阻滞剂abciximab,eptifibatide,tirofibanXa因子抑制剂占据新型抗凝药物的主导OralParenteral已经或即将进入临床的新型抗凝药物磺达肝癸钠Idrabiotaparinux利伐沙班

艾吡沙班Dabigatran口服制剂静脉制剂XaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenATAdaptedfromWeitz&Bates,JThrombHaemost2005研发中的IIa因子抑制剂Ximelagatran

Dabigatran口服制剂静脉制剂AdaptedfromWeitz&Bates,JThrombHaemost2005BivalirudinXaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogen修订的凝血模式

内源性凝血途径外源性凝血途径XIaIXaXaIIaVIIIaVa纤维蛋白原纤维蛋白血小板激活激活激活激活激活激活VIIa组织因子DavieEW.THEJOURNALOFBIOLOGICALCHEMISTRY.2003;278;51:50819–50832MonroeDM,etal.ArteriosclerThrombVascBiol.2006;26:41-48研发中的IIa因子抑制剂Ximelagatran

Dabigatran口服制剂静脉制剂AdaptedfromWeitz&Bates,JThrombHaemost2005BivalirudinXaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenDabigatran特征

DabigatranCompanyBoehringerIngelheimBrandnamePradaxaMechanismofactionDirectanti-IIa(Anti-Thrombin)ProdrugYesHalf-Life14-17hours(Stangierpubli)Anti-doteNo.NotNovoSeven®,but‘offlabel’FormulationHardcapsule,75and110mgRenalexcretion80%BiliaryexcretionLowDrugInteractionInteractionwithASAinhigherdoses.NointeractionwithcytochromeP450.NSAIDexcludedinclinicaltrials.P-glycoproteininhibitorsandenhancers.QuinidneCI.Amiodarone:dosereductionFoodInteractionDelayedabsorptionwithfoodBioavailabilityLow6%SpinalanesthesiaContra-indication,whileindwellingcatheterinplace.Start2hoursafterremovalSideeffectsVomiting17%(Lancet).Venousthrombosis.IndicationName(Phase)ComparatorDoseEndpointsCompletionResultsACSREDEEM(PhII)PlaceboDabigatran4dosesbidcompositeofmajorandclinicallyrelevantminorbleedingeventsduringsixmonthsoftreatmentQ32009AHA2009orACC2010SPAFRELYwarfarinDab110mg,150mgbidIncidenceofstrokeandsystemicembolismEndQ12009ESC2009Dabigatran临床研究

已完成的骨科领域研究：一项与美国克赛常用剂量(30mgBD)的对照研究失败；两项与克赛对照的研究证实为“非劣效性”剂量用法复杂几项进展中的临床研究（心血管领域）,包括:RE-LY:ANon-inferiorityTrialAtrialfibrillation≥1RiskFactorAbsenceofcontra-indications951centersin44countriesRWarfarinadjusted(INR2.0-3.0)N=6000DabigatranEtexilate110mgBIDN=6000DabigatranEtexilate150mgBIDN=6000BlindedEventAdjudication.OpenBlindedStrokeorSystemicEmbolism0.500.751.001.251.50Dabigatran110vs.WarfarinDabigatran150vs.WarfarinSuperiorityp-value

0.34<0.001HR(95%CI)WarfarinbetterDabigatranbetterBleedingD110mgD150mgwarfarinD110mgvs.WarfarinD150mgvs.WarfarinAnnualrateAnnualrateAnnualrateRR95%CIpRR95%CIpTotal14.6%16.4%18.2%0.780.74-0.83<0.0010.910.86-0.970.002Major2.7%3.1%3.4%0.800.69-0.930.0030.930.81-1.070.31Life-Threateningmajor1.2%1.5%1.8%0.680.55-0.83<0.0010.810.66-0.990.04Gastro-intestinalMajor1.1%1.5%1.0%1.100.86-1.410.431.501.19-1.89<0.001已经或即将进入临床的Xa因子抑制剂磺达肝癸钠Idrabiotaparinux利伐沙班

艾吡沙班口服制剂静脉制剂XaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenATAdaptedfromWeitz&Bates,JThrombHaemost2005Fondaparinus磺达肝癸钠IdrabiotaparinuxRivaroxaban利伐沙班Apixaban艾吡沙班Xa因子抑制剂Features利伐沙班艾吡沙班Molecularweight436460TargetFactorXaFactorXaProdrugNoNoCYP450metabolismMinimalMinimalTimetopeakdruglevel(h)33Half-life(h)99-14Biliaryexcretion(%)3575Renalexcretion(%)6525直接Xa抑制剂(口服)KneereplacementRivaroxaban10mgo.d.for12±2daysvs.

Enoxaparin30mgb.i.d.for12±2daysN=3148利伐沙班RECORD系列VTE预防III期研究Rivaroxaban10mgo.d.administered6–8hourspostsurgerycomparedwithenoxaparinSameefficacyandsafetyoutcomesSameindependent,blindedadjudicationcommitteesHipreplacementRivaroxaban10mgo.d.for35±4daysvs.

Enoxaparin40mgo.d.for35±4days

N=4541HipreplacementRivaroxaban10mgo.d.for35±4days

vs.

Enoxaparin40mgo.d.for12±2days

followedbyplaceboN=2509KneereplacementRivaroxaban10mgo.d.for12±2days

vs.

Enoxaparin40mgo.d.for12±2days

N=2531DatafromErikssonBIetal.NEnglJMed2008;358:2765–75;KakkarAKetal.Lancet2008;372:31–9;Lassen

MRetal.NEnglJMed2008;358:2776–86;TurpieAGGetal.PathophysiolHaemostThromb2007/2008;36:A14.利伐沙班-临床研究-VTETreatnent-AtrialFibrillation-ACStreatmentApixabanIII期临床试验（心血管领域）IndicationName(Phase)ComparatorDoseEndpointsTimeline/ResultsCommentsACSAPPRAISE–Ph1PlaceboApixaban2.5mgbid,10mgodBleeding-ISTHLineardoseresponsewithhigherbleeding/betterefficacywith10mgqd2.5mgbidtobetestedinphaseIIIIndicationTrialComparatorDoseEndpointsCompletionResultsSPAFARISTOTLE15000ptsAVERROES5600ptsWarfarin2mgINR2.5ASA–81-324mgqdupto36moApi2.5mg,5mgbidconfirmedstrokeorsystemicembolismQ32010Q42010ACSAPPRAISE-2/10800ptsplaceboApi5mgbidTimetofirstoccurrenceofcardiovasculardeath,MI,strokeQ42011Q12012已完成的临床试验进行中的临床试验FeaturesLMWH

磺达肝癸钠IdrabiotaparinuxRouteofadministrationSubcutaneousorintravenousSubcutaneousSubcutaneousTargetFactorXaandIIaFactorXaFactorXaBioavailability(%)90100100Half-life(h)417120Plasmaprotein-bindingLowNoneNoneRenalexcretionYesYesYesRiskofheparin-inducedthrombocytopeniaYesNoNoSafeinpregnancyYesUnknownUnknownNeutralizedbyprotaminesulfatePartialNoyes间接Xa因子抑制剂

生物素化戊糖(CASSIOPEA,赛诺菲-安万特)ProductProfileAnticoagulant(