《低分子肝素英》PPT课件.ppt

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1、5/98,MedS,1,Low-Molecular-Weight HeparinandUnfractionated Heparin,5/98,MedS,2,The 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

2、 fibrin clot,5/98,MedS,3,Coagulation Cascade,XIIa,XIa,IXa,Intrinsic Pathway(surface contact),Xa,Extrinsic Pathway(tissue factor),VIIa,Thrombin(IIa),Thrombin-FibrinClot,aPTT,PT,Heparin/LMWH(AT-III dependent),Hirudin/Hirulog(direct antithrombin),Courtesy of VTI,5/98,MedS,4,THROMBOSISCollagen XIaTissue

3、 Factor IXaPlatelet ClumpingThrombus FormationThrombus Growth,HEMOSTASISTissue Factor&CollagenPlatelet AggregationPlatelet-richHemostatic Plug,XaFluidThrombin,HEP,HEP&HIR,Heparin Inhibits Hemostasis,5/98,MedS,5,The Procoagulant State in Thrombolysis,Amplification,Vascular Injury,Activation of Platel

4、etsAnd Coagulation,Xa Thrombin(IIa),5/98,MedS,6,Low-molecular-weight heparin,UH(mw 3k-30k)is a heterogeneous mixture of polysacchride chains(glycosaminoglycans)LMWH(mw 5k)is obtained by alkaline degradation of heparin benzyl esterLMWH molecules are enriched with short chains with higher anti-Xa:IIa

5、ratio,5/98,MedS,7,Mechanism of Action,Both UH and LMWH exert their anticoagulation activity by catalyzing antithrombin(AT or AT III)catalyzed AT is accelerated in its inactivation of the coagulation enzymes thrombin(factor IIa)and factor Xa.prolongs aPTT,5/98,MedS,8,There are two heparin-cofactors,A

6、ntithrombin(AT)and Heparin Co-factor II(HC II).,AT is an effective antithrombinbut HC II is a very weak antithrombin,AT,HC II,+-,Interaction of Heparin Co-Factors with Thrombin,5/98,MedS,9,AT,HC II,+-,Interaction of Heparin Co-Factors with Thrombin,Heparin has a higher affinity for AT than for HC II

7、 and there is more AT in plasma than HC II,5/98,MedS,10,AT,Free Thrombin,Antithrombin and Free Thrombin,AT alone does not inactivate free-thrombin,5/98,MedS,11,Heparin binds to antithrombin and increases the rate of thrombin inactivation,AT,Heparin,Inactivation of Thrombin byHeparin-AT Complexes,5/9

8、8,MedS,12,AT,Fibrin-Bound Thrombin,The rate at which AT inactivatesfibrin-bound thrombin is reduced 50-fold,Effect of Antithrombin on Fibrin-Bound Thrombin,5/98,MedS,13,Inactivation of Thrombin by Heparin-AT Complexes,When thrombin binds to fibrin,it becomes resistant to inactivation by heparin.,Hep

9、arin,Fibrin,5/98,MedS,14,Mechanism of Action,SummaryCatalyzes ATIII Specific for fluid-phase thrombinProlongs aPTT by inactivating thrombin and blocking Xa generation,5/98,MedS,15,Differences in Mechanism of Action,Any size of heparin chain can inhibit the action of factor Xa by binding to antithrom

10、bin(AT)In contrast,in order to inactivate thrombin(IIa),the heparin molecule must be long enough to bind both antithrombin and thrombin half the chains of LMWH are long enough,5/98,MedS,16,AT,Unfractionated Heparin,Differential inhibitory activity against factor Xa and IIa activity,AT,LMWH,By bindin

11、g to AT,most UH and LMWH can inhibit Xa activity.Fewer than half the chains of LMWH are of sufficient length to also bind factor IIa,therefore has decreased anti-IIa activity.,5/98,MedS,17,Low-Molecular-Weight HeparinsAnti-Facotr Xa:Anti-Factor IIa Ratios,AgentTradeXa:IIaMol Wt(d)EnosaparinLovenox 3

12、.8:1 4,200DalteparinFragmin 2.7:1 6,000ArdeparinNormiflo 1.9:1 6,000Nadroparin 3.6:1 4,500Reviparin 3.5:1 4,000Tinzaparin 1.9:1 4,500,5/98,MedS,18,Advantages of LMWH over UH,Decreased“heparin resistance”pharmacokinetics of UH are influenced by its bindings to plasma protein,endothelial cell surfaces

13、,macrophages,and other acute phase reactantsLMWH has decreased binding to nonanticoagulant-related plasma proteins,5/98,MedS,19,Advantages of LMWH over UH,No need for laboratory monitoringwhen given on a weight-adjusted basis,the LMWH anticoagulant response is predictable and reproducibleHigher bioa

14、vailability-90%vs 30%Longer plasma half-life4 to 6 hours vs 0.5 to 1 hourrenal(slower)vs hepatic clearance,5/98,MedS,20,Advantages of LMWH over UH,Less inhibition of platelet functionpotentially less bleeding risk,but not shown in clinical useLower incidence of thrombocytopenia and thrombosis(HIT sy

15、ndrome)less interaction with platelet factor 4fewer heparin-dependent IgG antibodies,5/98,MedS,21,Monitoring of LMWH,Unnecessary in majority of patientsMay be useful in specific instancesrenal insufficiency(creatinine 2.0 mg/dl)obese patients with altered drug pKmajor bleeding risk factorsaPTT not u

16、seful-low anti-IIa activityanti-factor Xa assay is more appropriate,but not widely available,5/98,MedS,22,ESSENCE TrialEfficacy and Safety of SubcutaneousEnoxaparin in non-Q-Wave Coronary Events Study,A randomized study comparing the clinical efficacy of UFH vs enoxaparin LMWH in 3171 patients with

17、rest angina or non-Q-wave MIat 30 days,there was a relative risk reduction of 15%-16%in the rate of death,MI,or refractory ischemia as compared to standard heparin,N Eng J Med 1997;337:447-452,5/98,MedS,23,ESSENCE,Enoxaparin1.0 mg/kg q 12 hsubcutaneous,UFH5,000 U bolus+infaPTT 55-85 sec,Unstable Ang

18、inaNon-Q Wave MI,Acute Phasemin 48h,max 8 Days,30 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%NS,5/98,MedS,24,TIMI 11B-Study Design,Enoxaparin30 mg IV bolus+1.0

19、 mg/kg q 12 hsubcutaneous,UFH70 U/kg IV bolus+15U/Kg/h UFH IV,Unstable AnginaNon-Q Wave MI,Acute Phasemin 72h,max 8 Days,Chronic Phase,Fixed Dose 65 kg 40 mg 60 mg q 12 h,43 days,5/98,MedS,25,TIMI 11BLMWH in Unstable Angina,4,021 pts with acute coronary syndromeTwo treatment groups:UFH:70 U/kg bolus

20、 15 u/kg/hr iv LMWH:30 mg bolus 1 mg/kg s.q.bidPrimary endpoint(death,MI,urgent revascularization)48-72 hr26%14 days15%p0.03,Circulation 1999;100:1593-1601,5/98,MedS,26,Meta-AnalysisESSENCE and TIMI 11B,Primary endpoint Death/MI/Urgent RevscularizationOdds ratioRisk Reductionp-valDay 8 0.7121%0.02Da

21、y 14 0.7921%0.0005Day 43 0.8020%0.0006,European Society of Cardiology-August 1998,5/98,MedS,27,Primary Endpoint:Day 43Death/MI/Urgent Revasc,5/98,MedS,28,Difference 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

22、activity 3-5 2-4Dosing units mg IU,5/98,MedS,29,Enoxaparin in DVT Prophylaxis,DOSAGEDURATIONin patients undergoing30 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 dischar

23、gehip replacementin patients undergoing30 mg q12h SCaverage duration:7 to 10 daysknee-replacement surginitiate 12-24h postopin patients undergoing40 mg qd SCaverage duration:7 to 10 daysabdominal surgeryinitiate 2h preop,5/98,MedS,30,Enoxaparin in Treatment ofin acute DVT with or without PE,DOSAGEDU

24、RATIONFor patients who can be1 mg q12h SCcontinue LOVENOX for a treated at home for acute initiate warfarin sodiumminimal of 5 days and untilDVT without PEtherapy when appropriatea therapeutic oral anticoagulant(usually within 72h ofeffect has been achieved(INRLovenox administration)2.0 to 3.0).aver

25、age duration:7 days For hospitalized patients 1.5 mg/kg qd SC at the with acute DVT with or same time every day orwithout PE1 mg/kg q12h SC,5/98,MedS,31,Enoxaparin for UA and non-Q MI,DOSAGEDURATIONFor the prevention of1 mg/kg q12h SCminimum 2 days;usual duration ischemic complicationswith oral aspi

26、rin therapyof therapy:2 to 8 daysof unstable angina and(100 to 325 mg once daily)non-Q-wave myocardialinfarction(MI)whenconcurrently administeredwith aspirin,5/98,MedS,32,Economic Assessment of LMWH vs UFHResults from the ESSENCE Trail,enoxaparin heparinNeed for coronary angioplasty(initial)15%20%p=

27、.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 duration of treatment 2.3 daysmutidose vial enoxaparin-1 mg/kg at$0.38/mg,Circulation 1998;97:1702-1707,5/98,MedS,33,References,Lo

28、w-molecular weight heparins.Weitz JI.N Eng J Med 1997;337:688-698.Biochemistry and pharmacology of low molecular weight heparin.Rosenberg RD.Semin Hematol 1997;34(suppl 4):2-8.Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionaed heparin.Warkentin TE,Levine MN,Hirsh J,Horsewood P,Roberts RS,Gent M,et al.N Engl J Med 1995;332:1330-1335.Use of LMWH in the treatment of venous thromboembolic disease.Litin SC,Heit JA,Mees KA,for the Thrombophilia Center Investigators.Mayo Clin Proc 1998;73:545-551.,