1、5/00MedS1Low-Molecular-Weight HeparinandUnfractionated Heparin5/98MedS2The 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
2、 clot5/98MedS3Coagulation CascadeXIIaXIaIXaIntrinsic Pathway(surface contact)XaExtrinsic Pathway(tissue factor)VIIaThrombin(IIa)Thrombin-FibrinClotaPTTPTHeparin/LMWH(AT-III dependent)Hirudin/Hirulog(direct antithrombin)Courtesy of VTI 5/98MedS4THROMBOSISCollagen XIaTissue Factor IXaPlatelet Clumping
3、Thrombus FormationThrombus GrowthHEMOSTASISTissue Factor&CollagenPlatelet AggregationPlatelet-richHemostatic PlugXaFluidThrombinHeparin Inhibits Hemostasis5/98MedS5The Procoagulant State in ThrombolysisAmplificationVascular InjuryActivation of PlateletsAnd CoagulationXa Thrombin(IIa)5/98MedS6Low-mol
4、ecular-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 ester LMWH molecules are enriched with short chains with higher anti-Xa:IIa ratio5/98MedS7Mechanism of Action Both UH and LMWH exe
5、rt 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 aPTT5/98MedS8There are two heparin-cofactors,Antithrombin(AT)and Heparin Co-factor II(HC II).AT is an effect
6、ive antithrombinbut HC II is a very weak antithrombinATHC II+-Interaction of Heparin Co-Factors with ThrombinThrombinHFSCThrombinHFSC5/98MedS9ATHC II+-Interaction of Heparin Co-Factors with ThrombinThrombinHFSCThrombinHFSCHeparin has a higher affinity for AT than for HC II and there is more AT in pl
7、asma than HC II5/98MedS10ATFree ThrombinAntithrombin and Free ThrombinAT alone does not inactivate free-thrombinThrombinHFSC5/98MedS11Heparin binds to antithrombin and increases the rate of thrombin inactivationATHeparinInactivation of Thrombin byHeparin-AT ComplexesThrombinHFSC5/98MedS12ATFibrin-Bo
8、und ThrombinThe rate at which AT inactivatesfibrin-bound thrombin is reduced 50-foldEffect of Antithrombin on Fibrin-Bound ThrombinThrombinHFSC5/98MedS13Inactivation of Thrombin by Heparin-AT ComplexesWhen thrombin binds to fibrin,it becomes resistant to inactivation by heparin.ATHeparinFibrinThromb
9、inHFSC5/98MedS14Mechanism of Action Summary Catalyzes ATIII Specific for fluid-phase thrombin Prolongs aPTT by inactivating thrombin and blocking Xa generation5/98MedS15Differences in Mechanism of Action Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin(AT)In c
10、ontrast,in order to inactivate thrombin(IIa),the heparin 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 availab
11、le5/98MedS22ESSENCE 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 rest angina or non-Q-wave MI at 30 days,there was a relative risk reduction of 15%-16%in the r
12、ate of death,MI,or refractory ischemia as compared to standard heparinN Eng J Med 1997;337:447-4525/98MedS231.0 mg/kg q 12 h30 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
13、 d 2.9%3.6%NS5/98MedS2443 days5/98MedS25TIMI 11BLMWH in Unstable 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-
14、16015/98MedS26Meta-AnalysisESSENCE and TIMI 11BPrimary endpoint 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 19985/98MedS27Primary Endpoint:Day 43Death/MI/Urgent Revasc002244668810101212141
15、4161618182020004488121216162020242428283232363640404444P=0.048RRR 12%P=0.048P=0.048RRR 12%RRR 12%UFHUFHUFHENOXENOXENOX19.7%19.7%19.7%17.3%17.3%17.3%DaysDaysDays5/98MedS28Difference Between Lovenox and Heparin LovenoxHeparinHalf-life(hr)4.5 dose-dependentAnti-Xa:IIa 14:1 1:1Molecular wt(avg)4,500 15,
16、000Time to peak activity 3-5 2-4Dosing units mg IU4/00MedS29Enoxaparin in DVT ProphylaxisDOSAGEDURATIONin 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 p
17、ost dischargehip 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 preop4/00MedS30Enoxaparin in Treatment ofin acute DVT with or without PEDO
18、SAGEDURATIONFor 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
19、).average 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 SC4/00MedS31Enoxaparin for UA and non-Q MIDOSAGEDURATIONFor the prevention of1 mg/kg q12h SCminimum 2 days;usual duration ischemic complicationswith oral asp
20、irin therapyof therapy:2 to 8 daysof unstable angina and(100 to 325 mg once daily)non-Q-wave myocardialinfarction(MI)whenconcurrently administeredwith aspirin5/98MedS32Economic Assessment of LMWH vs UFHResults from the ESSENCE Trail enoxaparin heparinNeed for coronary angioplasty(initial)15%20%p=.04
21、 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/mgCirculation 1998;97:1702-17075/98MedS33ReferencesLow-molecul
22、ar 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.
