低分子肝素英文ppt課件

1、5/98;1The Coagulation Cascade Central to the coagulation cascade is the generation of thrombin (factor IIa) thrombin is generated from prothrombin by the action of activated factor X (Xa) thrombin then acts on fibrinogen to generate fibrin clot5/98;2Coagulation CascadeXIIaXIaIXaIntrinsic Pathway(sur

2、face contact)XaExtrinsic Pathway(tissue factor)VIIaThrombin (IIa)Thrombin-FibrinClotaPTTPTHeparin / LMWH(AT-III dependent)Hirudin/Hirulog(direct antithrombin)Courtesy of VTI 5/98;3THROMBOSISCollagen XIaTissue Factor IXaPlatelet ClumpingThrombus FormationThrombus GrowthHEMOSTASISTissue Factor &Co

3、llagenPlatelet AggregationPlatelet-richHemostatic PlugXaFluidThrombinHeparin Inhibits Hemostasis5/98;4The Procoagulant State in ThrombolysisAmplificationVascular InjuryActivation of PlateletsAnd CoagulationXa Thrombin (IIa)5/98;5Low-molecular-weight heparin UH (mw 3k - 30k) is a heterogeneous mixtur

4、e of polysacchride chains (glycosaminoglycans) LMWH (mw 5k) is obtained by alkaline degradation of heparin benzyl ester LMWH molecules are enriched with short chains with higher anti-Xa:IIa ratio5/98;6Mechanism of Action Both UH and LMWH exert their anticoagulation activity by catalyzing antithrombi

5、n (AT or AT III) catalyzed AT is accelerated in its inactivation of the coagulation enzymes thrombin (factor IIa) and factor Xa. prolongs aPTT5/98;7There are two heparin-cofactors, Antithrombin (AT) and Heparin Co-factor II (HC II).AT is an effective antithrombinbut HC II is a very weak antithrombin

6、ATHC II+- - - -Interaction of Heparin Co-Factors with ThrombinThrombinHFSCThrombinHFSC5/98;8ATHC II+- - - -Interaction of Heparin Co-Factors with ThrombinThrombinHFSCThrombinHFSCHeparin has a higher affinity for AT than for HC II and there is more AT in plasma than HC II5/98;9ATFree ThrombinAntithro

7、mbin and Free ThrombinAT alone does not inactivate free-thrombinThrombinHFSC5/98;10Heparin binds to antithrombin and increases the rate of thrombin inactivationATHeparinInactivation of Thrombin byHeparin-AT ComplexesThrombinHFSC5/98;11ATFibrin-Bound ThrombinThe rate at which AT inactivatesfibrin-bou

8、nd thrombin is reduced 50-foldEffect of Antithrombin on Fibrin-Bound ThrombinThrombinHFSC5/98;12Inactivation of Thrombin by Heparin-AT ComplexesWhen thrombin binds to fibrin, it becomes resistant to inactivation by heparin.ATHeparinFibrinThrombinHFSC5/98;13Mechanism of Action Summary Catalyzes ATIII

9、 Specific for fluid-phase thrombin Prolongs aPTT by inactivating thrombin and blocking Xa generation5/98;14Differences in Mechanism of Action Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT) In contrast, in order to inactivate thrombin (IIa), the heparin

10、molecule must be long enough to bind both antithrombin and thrombin 2.0 mg/dl) obese patients with altered drug pK major bleeding risk factors aPTT not useful - low anti-IIa activity anti-factor Xa assay is more appropriate, but not widely available5/98;21ESSENCE TrialEfficacy and Safety of Subcutan

11、eousEnoxaparin in non-Q-Wave Coronary Events Study A randomized study comparing the clinical efficacy of UFH vs enoxaparin LMWH in 3171 patients with rest angina or non-Q-wave MI at 30 days, there was a relative risk reduction of 15% -16% in the rate of death, MI, or refractory ischemia as compared

12、to standard heparinN Eng J Med 1997;337:447-4525/98;2230 days Enox HepIncidence of death, MI, angina14 d 16.6% 19.8% p=.01930 d 19.8% 23.3% p=.016Minor bleeding30 d 13.8% 8.8% p.001Major bleeding30 d 6.5% 7.0% NSDeath alone14 d 2.2% 2.3% NS30 d 2.9% 3.6% NS5/98;2343 days5/98;24TIMI 11BLMWH in Unstab

13、le Angina 4,021 pts with acute coronary syndrome Two treatment groups:UFH: 70 U/kg bolus 15 u/kg/hr iv LMWH: 30 mg bolus 1 mg/kg s.q. bid Primary endpoint(death, MI, urgent revascularization)48-72 hr26%14 days15%p0.03Circulation 1999; 100:1593-16015/98;25Meta-AnalysisESSENCE and TIMI 11BPrimary endp

14、oint Death / MI / Urgent RevscularizationOdds ratioRisk Reductionp-valDay 8 0.7121%0.02Day 14 0.7921%0.0005Day 43 0.8020%0.0006European Society of Cardiology - August 19985/98;26Primary Endpoint : Day 43Death/MI/Urgent Revasc002244668810101212141416161818202000448812121616202024242828323236364040444

15、4P=0.048RRR 12 %P=0.048P=0.048RRR 12 %RRR 12 %UFHUFHUFHENOXENOXENOX19.7 %19.7 %19.7 %17.3 %17.3 %17.3 %DaysDaysDays5/98;27Difference Between Lovenox and Heparin LovenoxHeparinHalf-life (hr) 4.5 dose-dependentAnti-Xa:IIa 14:1 1:1Molecular wt (avg) 4,500 15,000Time to peak activity 3-5 2-4Dosing units

16、 mg IU4/00;28Enoxaparin in DVT ProphylaxisDOSAGEDURATIONin patients undergoing 30 mg q12h SCaverage duration: 7 to 10 dayship-replacement surgeryinitiate 12-24h postopup to 14 days40 mg qd SCinitiated 12h (3) preopextended prophylaxis in40 mg qd SC3 weeks post dischargehip replacementin patients und

17、ergoing 30 mg q12h SCaverage duration: 7 to 10 daysknee-replacement surg initiate 12-24h postopin patients undergoing 40 mg qd SCaverage duration: 7 to 10 daysabdominal surgeryinitiate 2h preop4/00;29Enoxaparin in Treatment ofin acute DVT with or without PEDOSAGEDURATIONFor patients who can be1 mg q

18、12h SCcontinue LOVENOX for a treated at home for acute initiate warfarin sodiumminimal of 5 days and untilDVT without PEtherapy when appropriate a therapeutic oral anticoagulant (usually within 72h ofeffect has been achieved (INRLovenox administration)2.0 to 3.0).average duration: 7 days For hospita

19、lized patients 1.5 mg/kg qd SC at the with acute DVT with or same time every day orwithout PE1 mg/kg q12h SC4/00;30Enoxaparin for UA and non-Q MIDOSAGEDURATIONFor the prevention of1 mg/kg q12h SCminimum 2 days; usual duration ischemic complications with oral aspirin therapyof therapy: 2 to 8 daysof

20、unstable angina and (100 to 325 mg once daily)non-Q-wave myocardialinfarction (MI) whenconcurrently administeredwith aspirin5/98;31Economic Assessment of LMWH vs UFHResults from the ESSENCE Trail enoxaparin heparinNeed for coronary angioplasty (initial)15%20% p=.04 coronary angioplasty (30d)18%22% p=.08 diagnostic cath (30d)57%63% p=.04 Initial hospitalization mean drug cost in U.S.*$155$80 mean total cost of care$11,857$12,620mean du