血栓形成機制與抗栓藥物展望課件

血栓形成機制與抗栓藥物展望

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

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

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

低流速對血小板依賴程度很低靜脈

TMPGI2預防和治療靜脈系統(tǒng)血栓抗凝治療為主

血栓的類型動脈系統(tǒng)血栓形成高度依賴血小板抗血小板+抗凝治療心腔內(nèi)血栓形成對血小板依賴介入動靜脈之間高?；颊呖鼓委煘橹?，低?；颊呖寡“逯委熿o脈系統(tǒng)血栓形成對血小板依賴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

藥代動力學腸道吸收，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（氯吡格雷）血小板GPⅡb/Ⅲa拮抗劑作用機制

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GPIIbGPIIIaCa++GPIIIaGPIIb纖維蛋白原聚集X西洛他唑潘生丁作用機制

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GPIIbGPIIIaCa++GPIIIaGPIIb纖維蛋白原聚集奧扎格雷鈉安步樂克作用機制

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GPIIbGPIIIaCa++GPIIIaGPIIb纖維蛋白原聚集XPrasugrel抑制P2Y12藥代動力學迅速起效（≤

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第一種此類藥口服，長效阻斷血小板PAR–1受體不干擾纖維蛋白形成對出血時間或PT/aPTT無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OralParenteral已經(jīng)或即將進入臨床的新型抗凝藥物磺達肝癸鈉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

已完成的骨科領域研究：一項與美國克賽常用劑量(30mgBD)的對照研究失?。粌身椗c克賽對照的研究證實為“非劣效性”劑量用法復雜幾項進展中的臨床研究（心血管領域）,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)或即將進入臨床的Xa因子抑制劑磺達肝癸鈉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Xa抑制劑(口服)KneereplacementRivaroxaban10mgo.d.for12±2daysvs.

Enoxaparin30mgb.i.d.for12±2daysN=3148利伐沙班RECORD系列VTE預防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（心血管領域）IndicationName(Phase)ComparatorDoseEndpointsTimeline/ResultsCommentsACSAPPRAISE–Ph1PlaceboApixaban2.5mgbid,10mgodBleeding-ISTHLineardoseresponsewithhigherbleeding/betterefficacywith10mgqd2.5mgbidtobetestedinphaseIIIIndicationTrialComparatorDoseEndpointsCompletionResultsSPAFARISTOTLE15000ptsAVERROES5600ptsWarfarin2mgINR2.5ASA–81-324mgqdupto36moApi2.5mg,5mgbidconfirmedstrokeorsystemicembolismQ32010Q42010ACSAPPRAISE-2/10800ptsplaceboApi5mgbidTimetofirstoccurrenceofcardiovasculardeath,MI,strokeQ42011Q12012已完成的臨床試驗進行中的臨床試驗FeaturesLMWH

磺達肝癸鈉IdrabiotaparinuxRouteofadministrationSubcutaneousorintravenousSubcutaneousSubcutaneousTargetFactorXaandIIaFactorXaFactorXaBioavailability(%)90100100Half-life(h)417120Plasmaprotein-bindingLowNoneNoneRenalexcretionYesYesYesRiskofheparin-inducedthrombocytopeniaYesNoNoSafeinpregnancyYesUnknownUnknownNeutralizedbyprotaminesulfatePartialNoyes間接Xa因子抑制劑

生物素化戊糖(CASSIOPEA,賽諾菲-安萬特)ProductProfileAnticoagulant(