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Low-Molecular-Weight Heparin and Unfractionated Heparin

Low-Molecular-Weight Heparin and Unfractionated Heparin. 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)

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Low-Molecular-Weight Heparin and Unfractionated Heparin

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  1. Low-Molecular-Weight HeparinandUnfractionated Heparin MedSlides.com

  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 MedSlides.com

  3. Coagulation Cascade Intrinsic Pathway (surface contact) Extrinsic Pathway (tissue factor) XIIa VIIa XIa Heparin / LMWH(AT-III dependent) IXa Hirudin/Hirulog(direct antithrombin) Xa aPTT Thrombin (IIa) PT Thrombin-Fibrin Clot Courtesy of VTI MedSlides.com

  4. Heparin Inhibits Hemostasis THROMBOSIS Collagen   XIa Tissue Factor   IXa Platelet Clumping Thrombus Formation Thrombus Growth HEMOSTASIS Tissue Factor & Collagen Platelet Aggregation Platelet-rich Hemostatic Plug HEP Xa Fluid Thrombin HEP & HIR MedSlides.com

  5. The Procoagulant State in Thrombolysis Vascular Injury Activation of Platelets And Coagulation Amplification Xa Thrombin (IIa) MedSlides.com

  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 MedSlides.com

  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 MedSlides.com

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  9. F F H H Thrombin Thrombin S S C C Interaction of Heparin Co-Factors with Thrombin Heparin has a higher affinity for AT than for HC II and there is more AT in plasma than HC II AT HC II ++++ - - - - MedSlides.com

  10. F H Thrombin S C Antithrombin and Free Thrombin AT alone does not inactivate free-thrombin Free Thrombin AT MedSlides.com

  11. F H Thrombin S C Inactivation of Thrombin byHeparin-AT Complexes Heparin AT Heparin binds to antithrombin and increases the rate of thrombin inactivation MedSlides.com

  12. F H Thrombin S C Effect of Antithrombin on Fibrin-Bound Thrombin The rate at which AT inactivates fibrin-bound thrombin is reduced 50-fold Fibrin-Bound Thrombin AT MedSlides.com

  13. AT F H Thrombin S C Inactivation of Thrombin by Heparin-AT Complexes Fibrin Heparin When thrombin binds to fibrin, it becomes resistant to inactivation by heparin. MedSlides.com

  14. Mechanism of Action • Summary • Catalyzes ATIII • Specific for fluid-phase thrombin • Prolongs aPTT by inactivating thrombin and blocking Xa generation MedSlides.com

  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 • < half the chains of LMWH are long enough MedSlides.com

  16. F F H H Thrombin (IIa) Thrombin (IIa) S S C C Differential inhibitory activity against factor Xa and IIa activity Unfractionated Heparin LMWH AT AT By binding 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. MedSlides.com

  17. Low-Molecular-Weight HeparinsAnti-Facotr Xa : Anti - Factor IIa Ratios Agent Trade Xa:IIa Mol Wt (d) Enosaparin Lovenox 3.8 : 1 4,200 Dalteparin Fragmin 2.7 : 1 6,000 Ardeparin Normiflo 1.9 : 1 6,000 Nadroparin 3.6 : 1 4,500 Reviparin 3.5 : 1 4,000 Tinzaparin 1.9 : 1 4,500 MedSlides.com

  18. Advantages of LMWH over UH • Decreased “heparin resistance” • pharmacokinetics of UH are influenced by its bindings to plasma protein, endothelial cell surfaces, macrophages, and other acute phase reactants • LMWH has decreased binding to nonanticoagulant-related plasma proteins MedSlides.com

  19. Advantages of LMWH over UH • No need for laboratory monitoring • when given on a weight-adjusted basis, the LMWH anticoagulant response is predictable and reproducible • Higher bioavailability - 90% vs 30% • Longer plasma half-life • 4 to 6 hours vs 0.5 to 1 hour • renal (slower) vs hepatic clearance MedSlides.com

  20. Advantages of LMWH over UH • Less inhibition of platelet function • potentially less bleeding risk, but not shown in clinical use • Lower incidence of thrombocytopenia and thrombosis (HIT syndrome) • less interaction with platelet factor 4 • fewer heparin-dependent IgG antibodies MedSlides.com

  21. Monitoring of LMWH • Unnecessary in majority of patients • May be useful in specific instances • renal insufficiency (creatinine >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 MedSlides.com

  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 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 MedSlides.com

  23. 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 ESSENCE Enoxaparin 1.0 mg/kg q 12 h subcutaneous Unstable Angina Non-Q Wave MI UFH5,000 U bolus + infaPTT 55-85 sec Acute Phase min 48h, max 8 Days 30 days MedSlides.com

  24. Fixed Dose placebo q 12 h TIMI 11B - Study Design Fixed Dose < 65 kg > 65 kg 40 mg 60 mg q 12 h Enoxaparin 30 mg IV bolus + 1.0 mg/kg q 12 h subcutaneous Unstable Angina Non-Q Wave MI UFH 70 U/kg IV bolus + 15U/Kg/h UFH IV Acute Phase min 72h, max 8 Days Chronic Phase 43 days MedSlides.com

  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 hr 26% 14 days 15% p<0.03 Circulation 1999; 100:1593-1601 MedSlides.com

  26. Meta-AnalysisESSENCE and TIMI 11B Primary endpoint Death / MI / Urgent Revscularization Odds ratio Risk Reduction p-val Day 8 0.71 21% 0.02 Day 14 0.79 21% 0.0005 Day 43 0.80 20% 0.0006 European Society of Cardiology - August 1998 MedSlides.com

  27. Primary Endpoint : Day 43Death/MI/Urgent Revasc MedSlides.com

  28. Difference Between Lovenox and Heparin Lovenox Heparin Half-life (hr) 4.5 dose-dependent Anti-Xa:IIa 14:1 1:1 Molecular wt (avg) 4,500 15,000Time to peak activity 3-5 2-4Dosing units mg IU MedSlides.com

  29. Enoxaparin in DVT Prophylaxis DOSAGE DURATIONin patients undergoing 30 mg q12h SC average duration: 7 to 10 dayship-replacement surgery initiate 12-24h postop up to 14 days 40 mg qd SC initiated 12h (3) preopextended prophylaxis in 40 mg qd SC 3 weeks post dischargehip replacementin patients undergoing 30 mg q12h SC average duration: 7 to 10 daysknee-replacement surg initiate 12-24h postopin patients undergoing 40 mg qd SC average duration: 7 to 10 daysabdominal surgery initiate 2h preop MedSlides.com

  30. Enoxaparin in Treatment ofin acute DVT with or without PE DOSAGE DURATIONFor patients who can be 1 mg q12h SC continue LOVENOX for a treated at home for acute initiate warfarin sodium minimal of 5 days and untilDVT without PE therapy when appropriate a therapeutic oral anticoagulant (usually within 72h of effect has been achieved (INR Lovenox 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 PE 1 mg/kg q12h SC MedSlides.com

  31. Enoxaparin for UA and non-Q MI DOSAGE DURATIONFor the prevention of 1 mg/kg q12h SC minimum 2 days; usual duration ischemic complications with oral aspirin therapy of therapy: 2 to 8 daysof unstable angina and (100 to 325 mg once daily) non-Q-wave myocardialinfarction (MI) whenconcurrently administeredwith aspirin MedSlides.com

  32. Economic Assessment of LMWH vs UFHResults from the ESSENCE Trail enoxaparin heparin Need for coronary angioplasty (initial) 15% 20% p=.04 coronary angioplasty (30d) 18% 22% p=.08 diagnostic cath (30d) 57% 63% p=.04 Initial hospitalizationmean 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 MedSlides.com

  33. References • Low-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. MedSlides.com

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