Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,5/98,MedS,#,5/00,MedS,1,Low-Molecular-Weight HeparinandUnfractionated Heparin,5/00MedS1Low-Molecula,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 fibrin clot,5/98MedS2The Coagulat,5/98,MedS,3,Coagulation Cascade,XIIa,XIa,IXa,Intrinsic Pathway,(surface contact),Xa,Extrinsic Pathway,(tissue factor),VIIa,Thrombin(,IIa,),Thrombin-Fibrin,Clot,aPTT,PT,Heparin/LMWH,(AT-III dependent),Hirudin/Hirulog,(direct antithrombin),Courtesy of VTI,5/98MedS3Coagulation,5/98,MedS,4,THROMBOSIS,Collagen,XIa,Tissue Factor IXa,Platelet Clumping,Thrombus Formation,Thrombus Growth,HEMOSTASIS,Tissue Factor&Collagen,Platelet Aggregation,Platelet-rich,Hemostatic Plug,Xa,Fluid,Thrombin,HEP,HEP&HIR,Heparin Inhibits Hemostasis,5/98MedS4THROMBOSISHE,5/98,MedS,5,The Procoagulant State in Thrombolysis,Amplification,Vascular Injury,Activation of Platelets,And Coagulation,Xa,Thrombin(IIa),5/98MedS5The Procoagu,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 ester,LMWH molecules are enriched with short chains with higher anti-Xa:IIa ratio,5/98MedS6Low-molecula,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,5/98MedS7Mechanism of,5/98,MedS,8,There are two heparin-cofactors,Antithrombin(AT)and Heparin Co-factor II(HC II).,AT is an effective antithrombin,but HC II is a very weak antithrombin,AT,HC II,+,-,Interaction of Heparin Co-Factors with Thrombin,Thrombin,H,F,S,C,Thrombin,H,F,S,C,5/98MedS8There are tw,5/98,MedS,9,AT,HC II,+,-,Interaction of Heparin Co-Factors with Thrombin,Thrombin,H,F,S,C,Thrombin,H,F,S,C,Heparin has a higher affinity for AT than for HC II and there is more AT in plasma than HC II,5/98MedS9ATHC II+I,5/98,MedS,10,AT,Free Thrombin,Antithrombin and Free Thrombin,AT alone does not inactivate free-thrombin,Thrombin,H,F,S,C,5/98MedS10ATFree Thro,5/98,MedS,11,Heparin binds to antithrombin and increases the rate of thrombin inactivation,AT,Heparin,Inactivation of Thrombin byHeparin-AT Complexes,Thrombin,H,F,S,C,5/98MedS11Heparin bin,5/98,MedS,12,AT,Fibrin-Bound Thrombin,The rate at which AT inactivates,fibrin-bound thrombin is reduced 50-fold,Effect of Antithrombin on Fibrin-Bound Thrombin,Thrombin,H,F,S,C,5/98MedS12ATFibrin-Bo,5/98,MedS,13,Inactivation of Thrombin by Heparin-AT Complexes,When thrombin binds to fibrin,it becomes resistant to inactivation by heparin.,AT,Heparin,Fibrin,Thrombin,H,F,S,C,5/98MedS13Inactivatio,5/98,MedS,14,Mechanism of Action,Summary,Catalyzes ATIII,Specific for fluid-phase thrombin,Prolongs aPTT by inactivating thrombin and blocking Xa generation,5/98MedS14Mechanism o,5/98,MedS,15,Differences 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 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 available,5/98MedS21Monitoring,5/98,MedS,22,ESSENCE Trial,Efficacy 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 rate of death,MI,or refractory ischemia as compared to standard heparin,N Eng J Med 1997;337:447-452,5/98MedS22ESSENCE Tri,5/98,MedS,23,ESSENCE,Enoxaparin,1.0 mg/kg q 12 h,subcutaneous,UFH,5,000 U bolus+infaPTT 55-85 sec,Unstable Angina,Non-Q Wave MI,Acute Phase,min 48h,max 8 Days,30 days,Enox Hep,Incidence of death,MI,angina14 d,16.6%19.8%,p=.01930 d,19.8%23.3%,p=.016,Minor bleeding30 d,13.8%8.8%,p.001,Major bleeding30 d 6.5%7.0%NS,Death alone14 d 2.2%2.3%NS30 d 2.9%3.6%NS,5/98MedS23ESSENCE Eno,5/98,MedS,24,TIMI 11B-Study Design,Enoxaparin,30 mg IV bolus+,1.0 mg/kg q 12 h,subcutaneous,UFH,70 U/kg IV bolus+,15U/Kg/h UFH,IV,Unstable Angina,Non-Q Wave MI,Acute Phase,min 72h,max 8 Days,Chronic Phase,Fixed Dose,65 kg,40 mg 60 mg,q 12 h,Fixed Dose,placebo,q 12 h,43 days,5/98MedS24TIMI 11B-,5/98,MedS,25,TIMI 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%p0.03,Circulation