血栓形成機(jī)制與抗栓藥物展望.

1、血栓形成機(jī)制與抗栓藥物展望血栓形成機(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)院首都醫(yī)科大學(xué)附屬北京同仁醫(yī)院史旭波史旭波FibrinPlateletsRBCs血栓的構(gòu)成血栓的構(gòu)成 RBCs, red blood cells.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)烈抑血作用正常內(nèi)皮細(xì)胞有強(qiáng)烈抑血作用內(nèi)皮損傷誘發(fā)血栓形成示意圖內(nèi)皮損傷誘發(fā)血栓形成示意圖Pollack CV, et al. The Journal of Emergency Medicine. 2008(34)4: 417-42835 X 109典型血管的剪切率典型血管的剪切率血管類型血管類型剪切率剪切率 (

2、(s s-1-1) )靜脈靜脈20 -20020 -200大動脈大動脈300 - 800300 - 800小動脈小動脈500 - 1,600500 - 1,600狹窄冠狀動脈狹窄冠狀動脈800 - 10,000800 - 10,000動脈血栓形成動脈血栓形成高流速、高流速、高度依賴血小板高度依賴血小板動動脈脈 預(yù)防和治療動脈系統(tǒng)血栓預(yù)防和治療動脈系統(tǒng)血栓 抗血小板抗血小板+ +抗凝治療抗凝治療靜脈血栓形成靜脈血栓形成 低流速低流速 對血小板依賴程度很低對血小板依賴程度很低靜靜脈脈預(yù)防和治療靜脈系統(tǒng)血栓預(yù)防和治療靜脈系統(tǒng)血栓抗凝治療為主抗凝治療為主 動脈系統(tǒng)血栓形成動脈系統(tǒng)血栓形成高度依賴血小板

3、高度依賴血小板抗血小板抗血小板+抗凝治療抗凝治療 心腔內(nèi)血栓形成心腔內(nèi)血栓形成對血小板依賴介入動靜脈之間對血小板依賴介入動靜脈之間高?；颊呖鼓委煘橹?，低?；颊呖寡“逯委煾呶；颊呖鼓委煘橹?，低危患者抗血小板治療 靜脈系統(tǒng)血栓形成靜脈系統(tǒng)血栓形成對血小板依賴較低對血小板依賴較低抗凝治療為主抗凝治療為主Brass, L. F. Chest 2003;124:18-25S血小板的作用血小板的作用 抗血小板藥物抗血小板藥物 血栓素血栓素 A A2 2 抑制劑抑制劑阿司匹林阿司匹林 ( (ASA)ASA) ADP-ADP-受體拮抗劑受體拮抗劑氯吡格雷氯吡格雷 噻氯匹啶噻氯匹啶 糖蛋白糖蛋白 ( (G

4、P) IIb/IIIa GP) IIb/IIIa 阻滯劑阻滯劑abciximab, eptifibatide, tirofibanabciximab, eptifibatide, tirofiban阿司匹林的抗血小板作用阿司匹林的抗血小板作用膠原膠原 5-羥色氨羥色氨 ADP凝血酶凝血酶 TXA2刺激傳刺激傳遞系統(tǒng)遞系統(tǒng)腎上腺素腎上腺素 cAMPCa+釋放反應(yīng)釋放反應(yīng)GP IIbGP IIIaCa+GP IIIaGP IIb纖維蛋白原纖維蛋白原聚集聚集AspirinAntithrombotic Trialists Collaboration. BMJ. 2002;324:71-86.00.51

5、.01.52.05001500 mg34 19160325 mg19 2675150 mg12 3275 mg 3 13Any aspirin65 23Antiplatelet BetterAntiplatelet WorseAspirin Dose # Trials OR* (%)*Odds reduction. Treatment effect P 0.0001.Odds Ratio氯吡格雷作用機(jī)制氯吡格雷作用機(jī)制 膠原膠原 5-羥色氨羥色氨 ADP凝血酶凝血酶 TXA2刺激傳刺激傳遞系統(tǒng)遞系統(tǒng)腎上腺素腎上腺素 cAMPCa+釋放反應(yīng)釋放反應(yīng)GP IIbGP IIIaCa+GP IIIaG

6、P IIb纖維蛋白原纖維蛋白原聚集聚集X藥藥 代代 動動 力力 學(xué)學(xué) 腸道吸收，肝臟代謝，腸道吸收，肝臟代謝，2.2% 2.4% 尿中排泄尿中排泄 半減期為半減期為 7.2 7.5 小時小時 75mg/d, 4 5天天; 300mg/d, 4-6h; 600mg/d, 2h 停藥后作用可延續(xù)到停藥后作用可延續(xù)到 7 10到穩(wěn)定天，洗脫期長到穩(wěn)定天，洗脫期長 （氯吡格雷）血小板血小板 GPb / a 拮抗劑作用機(jī)制拮抗劑作用機(jī)制 膠原膠原 5-羥色氨羥色氨 ADP凝血酶凝血酶 TXA2刺激傳刺激傳遞系統(tǒng)遞系統(tǒng)腎上腺素腎上腺素 cAMPCa+釋放反應(yīng)釋放反應(yīng)GP IIbGP IIIaCa+GP I

7、IIaGP IIb纖維蛋白原纖維蛋白原聚集聚集X西洛他唑西洛他唑 潘生丁作用機(jī)制潘生丁作用機(jī)制 膠原膠原 5-羥色氨羥色氨 ADP凝血酶凝血酶 TXA2刺激傳刺激傳遞系統(tǒng)遞系統(tǒng)腎上腺素腎上腺素 cAMPCa+釋放反應(yīng)釋放反應(yīng)GP IIbGP IIIaCa+GP IIIaGP IIb纖維蛋白原纖維蛋白原聚集聚集X奧扎格雷鈉的抗血小板作用奧扎格雷鈉的抗血小板作用膠原膠原 5-羥色氨羥色氨 ADP凝血酶凝血酶 TXA2刺激傳刺激傳遞系統(tǒng)遞系統(tǒng)腎上腺素腎上腺素 cAMPCa+釋放反應(yīng)釋放反應(yīng)GP IIbGP IIIaCa+GP IIIaGP IIb纖維蛋白原纖維蛋白原聚集聚集奧扎格雷鈉安步樂克作用機(jī)制

8、安步樂克作用機(jī)制 膠原膠原 5-羥色氨羥色氨 ADP凝血酶凝血酶 TXA2刺激傳刺激傳遞系統(tǒng)遞系統(tǒng)腎上腺素腎上腺素 cAMPCa+釋放反應(yīng)釋放反應(yīng)GP IIbGP IIIaCa+GP IIIaGP IIb纖維蛋白原纖維蛋白原聚集聚集XNew Antiplatelet Agents P 2 Y 12 antagonists Prasugrel Ticagrelor Cangrelor Thrombin receptor antagonists SCH 530348 E 5555Prasugrel 抑制 P 2 Y 12 藥代動力學(xué) 迅速起效（ 2 h） 不可逆的結(jié)合 與氯吡格雷激活的代謝途徑不同

9、 比氯吡格雷更有效的抑制 ADP 引起的血小板激活TicagrelorPrimary endpoint: CV death, MI or stroke005101560120180240300360Days after randomizationK-M estimated rate (% per year)HR: 0.84 (95% CI = 0.750.94), p=0.00259.0210.65ClopidogrelTicagrelorNo. at riskClopidogrelTicagrelor6,6766,7326,1296,2366,0346,1345,8814,8154,8893

10、,6803,7352,9653,0485,972K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval TicagrelorClopidogrelNSNSNS0K-M estimated rate (% per year)PLATO major bleeding12345678910121113TIMI major bleeding11.511.68.08.02.93.2GUSTO severe bleeding*4.74.12.82.31.91.7Non-CABG and CABG-related major bleed

11、ingNon-CABGCABG*Preliminary from eCRF凝血酶受體拮抗劑凝血酶受體拮抗劑 TRA SCH 530348 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, tirofibanOralParenteral 磺達(dá)肝癸鈉磺達(dá)肝癸鈉Idrabiotaparinux利伐沙班利伐沙班艾吡沙班艾吡沙班Dabigatran口服制劑

12、口服制劑靜脈制劑靜脈制劑XaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenATAdapted from Weitz & Bates, J Thromb Haemost 2005XimelagatranDabigatran口服制劑口服制劑靜脈制劑靜脈制劑Adapted from Weitz & Bates, J Thromb Haemost 2005BivalirudinXaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenDavie EW. THE JOURNAL OF BIOLOGICAL CHEMISTRY

13、.2003;278;51:5081950832Monroe DM, et al. Arterioscler Thromb Vasc Biol. 2006;26:41-48XimelagatranDabigatran口服制劑口服制劑靜脈制劑靜脈制劑Adapted from Weitz & Bates, J Thromb Haemost 2005BivalirudinXaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenDabigatranCompanyBoehringer IngelheimBrand namePradaxa Mechanism of ac

14、tionDirect anti-IIa (Anti-Thrombin)ProdrugYesHalf-Life14-17 hours (Stangier publi)Anti-doteNo. Not NovoSeven, but off labelFormulationHard capsule, 75 and 110 mgRenal excretion80%Biliary excretionLowDrug InteractionInteraction with ASA in higher doses. No interaction with cytochrome P450.NSAID exclu

15、ded in clinical trials. P-glycoprotein inhibitors and enhancers. Quinidne CI. Amiodarone: dose reductionFood InteractionDelayed absorption with foodBioavailabilityLow 6%Spinal anesthesiaContra-indication, while indwelling catheter in place. Start 2 hours after removalSide effectsVomiting 17% (Lancet

16、). Venous thrombosis.IndicationName (Phase)ComparatorDoseEndpointsCompletionResultsACSREDEEM (Ph II)PlaceboDabigatran 4 doses bidcomposite of major and clinically relevant minor bleeding events during six months of treatment Q3 2009AHA 2009 o r A C C 2010SPAFRELYwarfarinDab 110mg, 150mg bidIncidence

17、 of stroke and systemic embolismEnd Q1 2009ESC 2009Dabigatran臨床研究臨床研究 已完成的骨科領(lǐng)域研究：已完成的骨科領(lǐng)域研究： 一項(xiàng)與美國克賽常用劑量一項(xiàng)與美國克賽常用劑量(30mg BD) 的對照研究失??；的對照研究失敗； 兩項(xiàng)與克賽對照的研究證實(shí)為兩項(xiàng)與克賽對照的研究證實(shí)為“非劣效性非劣效性” 劑量用法復(fù)雜劑量用法復(fù)雜 幾項(xiàng)進(jìn)展中的臨床研究（心血管領(lǐng)域）幾項(xiàng)進(jìn)展中的臨床研究（心血管領(lǐng)域）, 包括包括:RE-LY: A Non-inferiority TrialAtrial fibrillation 1 Risk FactorAbse

18、nce of contra-indications951 centers in 44 countriesRWarfarinadjusted (INR 2.0-3.0)N=6000Dabigatran Etexilate 110 mg BIDN=6000Dabigatran Etexilate 150 mg BIDN=6000Blinded Event Adjudication.OpenBlindedStroke or Systemic Embolism0.500.751.001.251.50Dabigatran 110 vs. WarfarinDabigatran 150 vs. Warfar

19、inSuperiorityp-value 0.340.001HR (95% CI)Warfarin betterDabigatran betterBleedingD 110mgD 150mgwarfarinD 110mg vs. WarfarinD 150mg vs. WarfarinTotal14.6%16.4%18.2%0.780.74-0.830.0010.910.86-0.970.002Major 2.7 %3.1 %3.4 %0.800.69-0.930.0030.930.81-1.070.31Life-Threatening major1.2 %1.5 %1.8 %0.680.55

20、-0.830.0010.810.66-0.990.04Gastro-intestinalMajor1.1 %1.5 %1.0 %1.100.86-1.410.431.501.19-1.890.001磺達(dá)肝癸鈉磺達(dá)肝癸鈉Idrabiotaparinux利伐沙班利伐沙班艾吡沙班艾吡沙班口服制劑口服制劑靜脈制劑靜脈制劑XaIIaTF/VIIaXIXIXaVIIIaVaIIFibrinFibrinogenATAdapted from Weitz & Bates, J Thromb Haemost 2005Fondaparinus 磺達(dá)肝癸鈉磺達(dá)肝癸鈉IdrabiotaparinuxRivaro

21、xaban 利伐沙班利伐沙班Apixaban 艾吡沙班艾吡沙班Features利伐沙班利伐沙班艾吡沙班艾吡沙班Molecular weight436460TargetFactor XaFactor XaProdrugNoNoCYP450 metabolismMinimalMinimalTime to peak drug level (h)33Half-life (h)99- 14Biliary excretion (%)3575Renal excretion (%)6525直接直接 Xa 抑制劑抑制劑 (口服口服)Knee replacementRivaroxaban 10 mg o.d.fo

22、r 12 2 daysvs.Enoxaparin 30 mg b.i.d.for 12 2 days N = 3148 Rivaroxaban 10 mg o.d. administered 68 hours post surgery compared with enoxaparin Same efficacy and safety outcomes Same independent, blinded adjudication committeesHip replacementRivaroxaban 10 mg o.d.for 35 4 daysvs.Enoxaparin 40 mg o.d.

23、for 35 4 daysN = 4541Hip replacementRivaroxaban 10 mg o.d.for 35 4 days vs.Enoxaparin 40 mg o.d.for 12 2 days followed by placeboN = 2509Knee replacementRivaroxaban 10 mg o.d.for 12 2 days vs.Enoxaparin 40 mg o.d.for 12 2 days N = 2531Data from Eriksson BI et al. N Engl J Med 2008;358:276575; Kakkar

24、 AK et al. Lancet 2008;372:319; Lassen MR et al. N Engl J Med 2008;358:277686; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14. - VTE Treatnent- Atrial Fibrillation- ACS treatmentIndicationName (Phase)ComparatorDoseEndpointsTimeline/ResultsCommentsACSAPPRAISE Ph1PlaceboApixaban 2.5mg

25、bid, 10mg odBleeding - ISTHLinear dose response with higher bleeding /better efficacy with 10mg qd2.5mg bid to be tested in phase IIIIndicationTrialComparatorDoseEndpointsCompletionResultsSPAF ARISTOTLE 15000 ptsAVERROES 5600 ptsWarfarin 2mg INR 2.5ASA 81-324 mg qd upto 36 moApi 2.5mg, 5mg bidconfir

26、med stroke or systemic embolismQ3 2010Q4 2010ACSAPPRAISE-2 /10800 ptsplaceboApi 5mg bid Time to first occurrence of cardiovascular death, MI, strokeQ4 2011Q1 2012已完成的臨床試驗(yàn)已完成的臨床試驗(yàn)進(jìn)行中的臨床試驗(yàn)進(jìn)行中的臨床試驗(yàn)FeaturesLMWH 磺達(dá)磺達(dá)肝癸鈉肝癸鈉IdrabiotaparinuxRoute of administrationSubcutaneous or intravenousSubcutaneousSubcu

27、taneousTargetFactor Xa and IIaFactor XaFactor XaBioavailability (%)90100100Half-life (h)417120Plasma protein-bindingLowNoneNoneRenal excretionYesYesYesRisk of heparin- induced thrombocytopeniaYesNoNoSafe in pregnancyYesUnknownUnknownNeutralized by protamine sulfatePartialNoyes間接間接 CASSIOPEAProduct ProfileAnticoag