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 fi
2、brin 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 C
3、lumpingThrombus FormationThrombus GrowthHEMOSTASISTissue Factor &CollagenPlatelet AggregationPlatelet-richHemostatic PlugXaFluidThrombinHeparin Inhibits Hemostasis5/98MedS5The Procoagulant State in ThrombolysisAmplificationVascular InjuryActivation of PlateletsAnd CoagulationXa Thrombin (IIa)5/98Med
4、S6Low-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 ester LMWH molecules are enriched with short chains with higher anti-Xa:IIa ratio5/98MedS7Mechanism of Action Bot
5、h 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 aPTT5/98MedS8There are two heparin-cofactors, Antithrombin (AT) and Heparin Co-factor
6、II (HC II).AT is an effective 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 tha
7、n for HC II and there is more AT in plasma 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 Comp
8、lexesThrombinHFSC5/98MedS12ATFibrin-Bound 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 inacti
9、vation by heparin.ATHeparinFibrinThrombinHFSC5/98MedS14Mechanism 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 facto
10、r Xa by binding to antithrombin (AT) In contrast, 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 a
11、ssay is more appropriate, but not widely available5/98MedS22ESSENCE 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
12、 was a relative risk reduction of 15% -16% in the rate 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
13、.001Major bleeding30 d 6.5% 7.0% NSDeath alone14 d 2.2% 2.3% NS30 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, urgen
14、t revascularization)48-72 hr26%14 days15%p0.03Circulation 1999; 100:1593-16015/98MedS26Meta-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 1
15、9985/98MedS27Primary Endpoint : Day 43Death/MI/Urgent Revasc0022446688101012121414161618182020004488121216162020242428283232363640404444P=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 L
16、ovenoxHeparinHalf-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 mg IU4/00MedS29Enoxaparin in DVT ProphylaxisDOSAGEDURATIONin patients undergoing30 mg q12h SCaverage duration: 7 to 10 dayship-replacement surgeryinitiate 12-24h
17、 postopup to 14 days40 mg qd SCinitiated 12h (3) preopextended prophylaxis in40 mg qd SC3 weeks post 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 daysabdo
18、minal surgeryinitiate 2h preop4/00MedS30Enoxaparin in Treatment ofin acute DVT with or without PEDOSAGEDURATIONFor 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 or
19、al anticoagulant (usually within 72h ofeffect has been achieved (INRLovenox administration)2.0 to 3.0).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 MIDOSAGEDURATIO
20、NFor the prevention of1 mg/kg q12h SCminimum 2 days; usual duration ischemic complicationswith oral aspirin 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 LMW
21、H 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 duration of treatment
22、 2.3 daysmutidose vial enoxaparin - 1 mg/kg at $0.38/mgCirculation 1998;97:1702-17075/98MedS33ReferencesLow-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
23、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.
