血栓形成機(jī)制與抗栓藥物展望課件

血栓形成機(jī)制與抗栓藥物展望

首都醫(yī)科大學(xué)附屬北京同仁醫(yī)院史旭波FibrinPlateletsRBCs血栓的構(gòu)成

RBCs,redbloodcells.血栓是機(jī)體維護(hù)血管壁結(jié)構(gòu)完整的一種防護(hù)性反應(yīng)正常內(nèi)皮細(xì)胞有強(qiáng)烈抑血作用典型血管的剪切率血管類(lèi)型剪切率(s-1)靜脈20-200大動(dòng)脈300-800小動(dòng)脈500-1,600狹窄冠狀動(dòng)脈800-10,000動(dòng)脈血栓形成高流速、高度依賴(lài)血小板動(dòng)脈

TMPGI2預(yù)防和治療動(dòng)脈系統(tǒng)血栓抗血小板+抗凝治療靜脈血栓形成

低流速對(duì)血小板依賴(lài)程度很低靜脈

TMPGI2預(yù)防和治療靜脈系統(tǒng)血栓抗凝治療為主

血栓的類(lèi)型動(dòng)脈系統(tǒng)血栓形成高度依賴(lài)血小板抗血小板+抗凝治療心腔內(nèi)血栓形成對(duì)血小板依賴(lài)介入動(dòng)靜脈之間高危患者抗凝治療為主，低危患者抗血小板治療靜脈系統(tǒng)血栓形成對(duì)血小板依賴(lài)較低抗凝治療為主阿司匹林的抗血小板作用膠原

5-羥色氨

ADP凝血酶

TXA2刺激傳遞系統(tǒng)腎上腺素

cAMPCa++釋放反應(yīng)GPIIbGPIIIaCa++GPIIIaGPIIb纖維蛋白原聚集Aspirin

ACS患者阿司匹林的適宜劑量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

藥代動(dòng)力學(xué)腸道吸收，肝臟代謝，2.2%~2.4%尿中排泄半減期為7.2~7.5小時(shí)75mg/d,

4–5天;300mg/d,4-6h;600mg/d,2h停藥后作用可延續(xù)到7~10到穩(wěn)定天，洗脫期長(zhǎng)（氯吡格雷）血小板GPⅡb/Ⅲa拮抗劑作用機(jī)制

膠原

5-羥色氨

ADP凝血酶

TXA2刺激傳遞系統(tǒng)腎上腺素

cAMPCa++釋放反應(yīng)GPIIbGPIIIaCa++GPIIIaGPIIb纖維蛋白原聚集X西洛他唑潘生丁作用機(jī)制

膠原

5-羥色氨

ADP凝血酶

TXA2刺激傳遞系統(tǒng)腎上腺素

cAMPCa++釋放反應(yīng)GPIIbGPIIIaCa++GPIIIaGPIIb纖維蛋白原聚集X奧扎格雷鈉的抗血小板作用膠原

5-羥色氨

ADP凝血酶

TXA2刺激傳遞系統(tǒng)腎上腺素

cAMPCa++釋放反應(yīng)GPIIbGPIIIaCa++GPIIIaGPIIb纖維蛋白原聚集奧扎格雷鈉安步樂(lè)克作用機(jī)制

膠原

5-羥色氨

ADP凝血酶

TXA2刺激傳遞系統(tǒng)腎上腺素

cAMPCa++釋放反應(yīng)GPIIbGPIIIaCa++GPIIIaGPIIb纖維蛋白原聚集XPrasugrel抑制P2Y12藥代動(dòng)力學(xué)迅速起效（≤

2h）不可逆的結(jié)合與氯吡格雷激活的代謝途徑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凝血酶受體拮抗劑TRASCH530348第一種此類(lèi)藥口服，長(zhǎng)效阻斷血小板PAR–1受體不干擾纖維蛋白形成對(duì)出血時(shí)間或PT/aPTT無(wú)影響抗血小板藥物血栓素A2抑制劑阿司匹林(ASA)ADP-受體拮抗劑氯吡格雷噻氯匹啶糖蛋白(GP)IIb/IIIa阻滯劑abciximab,eptifibatide,tirofibanXa因子抑制劑占據(jù)新型抗凝藥物的主導(dǎo)OralParenteral已經(jīng)或即將進(jìn)入臨床的新型抗凝藥物磺達(dá)肝癸鈉Idrabiotaparinux利伐沙班

艾吡沙班Dabigatran口服制劑靜脈制劑XaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenATAdaptedfromWeitz&Bates,JThrombHaemost2005研發(fā)中的IIa因子抑制劑Ximelagatran

Dabigatran口服制劑靜脈制劑AdaptedfromWeitz&Bates,JThrombHaemost2005BivalirudinXaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogen修訂的凝血模式

內(nèi)源性凝血途徑外源性凝血途徑XIaIXaXaIIaVIIIaVa纖維蛋白原纖維蛋白血小板激活激活激活激活激活激活VIIa組織因子DavieEW.THEJOURNALOFBIOLOGICALCHEMISTRY.2003;278;51:50819–50832MonroeDM,etal.ArteriosclerThrombVascBiol.2006;26:41-48研發(fā)中的IIa因子抑制劑Ximelagatran

Dabigatran口服制劑靜脈制劑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臨床研究

已完成的骨科領(lǐng)域研究：一項(xiàng)與美國(guó)克賽常用劑量(30mgBD)的對(duì)照研究失?。粌身?xiàng)與克賽對(duì)照的研究證實(shí)為“非劣效性”劑量用法復(fù)雜幾項(xiàng)進(jìn)展中的臨床研究（心血管領(lǐng)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已經(jīng)或即將進(jìn)入臨床的Xa因子抑制劑磺達(dá)肝癸鈉Idrabiotaparinux利伐沙班

艾吡沙班口服制劑靜脈制劑XaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenATAdaptedfromWeitz&Bates,JThrombHaemost2005Fondaparinus磺達(dá)肝癸鈉IdrabiotaparinuxRivaroxaban利伐沙班Apixaban艾吡沙班Xa因子抑制劑Features利伐沙班艾吡沙班Molecularweight436460TargetFactorXaFactorXaProdrugNoNoCYP450metabolismMinimalMinimalTimetopeakdruglevel(h)33Half-life(h)99-14Biliaryexcretion(%)3575Renalexcretion(%)6525直接X(jué)a抑制劑(口服)KneereplacementRivaroxaban10mgo.d.for12±2daysvs.

Enoxaparin30mgb.i.d.for12±2daysN=3148利伐沙班RECORD系列VTE預(yù)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-臨床研究-VTETreatnent-AtrialFibrillation-ACStreatmentApixabanIII期臨床試驗(yàn)（心血管領(lǐng)域）IndicationName(Phase)ComparatorDoseEndpointsTimeline/ResultsCommentsACSAPPRAISE–Ph1PlaceboApixaban2.5mgbid,10mgodBleeding-ISTHLineardoseresponsewithhigherbleeding/betterefficacywith10mgqd2.5mgbidtobetestedinphaseIIIIndicationTrialComparatorDoseEndpointsCompletionResultsSPAFARISTOTLE15000ptsAVERROES5600ptsWarfarin2mgINR2.5ASA–81-324mgqdupto36moApi2.5mg,5mgbidconfirmedstrokeorsystemicembolismQ32010Q42010ACSAPPRAISE-2/10800ptsplaceboApi5mgbidTimetofirstoccurrenceofcardiovasculardeath,MI,strokeQ42011Q12012已完成的臨床試驗(yàn)進(jìn)行中的臨床試驗(yàn)FeaturesLMWH

磺達(dá)肝癸鈉IdrabiotaparinuxRouteofadministrationSubcutaneousorintravenousSubcutaneousSubcutaneousTargetFactorXaandIIaFactorXaFactorXaBioavailability(%)90100100Half-life(h)417120Plasmaprotein-bindingLowNoneNoneRenalexcretionYesYesYesRiskofheparin-inducedthrombocytopeniaYesNoNoSafeinpregnancyYesUnknownUnknownNeutralizedbyprotaminesulfatePartialNoyes間接X(jué)a因子抑制劑

生物素化戊糖(CASSIOPEA,賽諾菲-安萬(wàn)特)ProductProfileAnticoagulant(