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Low-Molecular-Weight Heparinand
Unfractionated Heparin
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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
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Coagulation CascadeCoagulation 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
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THROMBOSISCollagen XIa
Tissue Factor IXa
Platelet Clumping
Thrombus Formation
Thrombus Growth
HEMOSTASIS
Tissue Factor &Collagen
Platelet Aggregation
Platelet-richHemostatic Plug
Xa
FluidThrombin
HEPHEP
HEP & HIRHEP & HIR
Heparin Inhibits HemostasisHeparin Inhibits Hemostasis
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The Procoagulant State in Thrombolysis
The Procoagulant State in Thrombolysis
Amplification
Vascular Injury
Activation of PlateletsAnd Coagulation
Xa
Thrombin (IIa)
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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
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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
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AT
HC II
++++- - -
-
Interaction of Heparin Co-Factors with Thrombin
Interaction of Heparin Co-Factors with Thrombin
ThrombinHF
S C
ThrombinHF
S C
Heparin has a higher affinity for AT than for HC II and there is more AT in plasma than HC II
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AT
Free Thrombin
Antithrombin and Free ThrombinAntithrombin and Free Thrombin
AT alone does not inactivate free-thrombin
ThrombinHF
S C
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Heparin binds to antithrombin and increases the rate of thrombin inactivation
AT
Heparin
Inactivation of Thrombin byHeparin-AT Complexes
Inactivation of Thrombin byHeparin-AT Complexes
ThrombinHF
S C
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AT
Fibrin-Bound Thrombin
The rate at which AT inactivatesfibrin-bound thrombin is reduced 50-fold
Effect of Antithrombin on Fibrin-Bound Thrombin
Effect of Antithrombin on Fibrin-Bound Thrombin
ThrombinHF
S C
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Inactivation of Thrombin by Heparin-AT Complexes
Inactivation of Thrombin by Heparin-AT Complexes
When thrombin binds to fibrin, it becomes resistant to inactivation by heparin.
AT
HeparinFibrin
ThrombinHF
S C
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Mechanism of Action
• Summary– Catalyzes ATIII – Specific for fluid-phase thrombin– Prolongs aPTT by inactivating thrombin and
blocking Xa generation
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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
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AT
Unfractionated Heparin
Differential inhibitory activity against factor Xa and IIa activity
Differential inhibitory activity against factor Xa and IIa activity
Thrombin (IIa)HF
S C AT
LMWH
Thrombin (IIa)HF
S C
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.
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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
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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
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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
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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
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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
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ESSENCE TrialEfficacy and Safety of Subcutaneous
Enoxaparin 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
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ESSENCE ESSENCE
EnoxaparinEnoxaparin1.0 mg/kg q 12 hsubcutaneoussubcutaneous
UFHUFH5,000 U bolus + inf5,000 U bolus + inf
aPTT 55-85 secaPTT 55-85 sec
Unstable AnginaUnstable AnginaNon-Q Wave MINon-Q Wave MI
Acute PhaseAcute Phasemin 48h, max 8 Daysmin 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
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TIMI 11B - Study DesignTIMI 11B - Study Design
EnoxaparinEnoxaparin30 mg IV bolus +30 mg IV bolus +1.0 mg/kg q 12 h1.0 mg/kg q 12 hsubcutaneoussubcutaneous
UFHUFH70 U/kg IV bolus +70 U/kg IV bolus +
15U/Kg/h UFH 15U/Kg/h UFH IVIV
Unstable AnginaUnstable AnginaNon-Q Wave MINon-Q Wave MI
Acute PhaseAcute Phasemin 72h, max 8 Daysmin 72h, max 8 Days
Chronic PhaseChronic Phase
Fixed DoseFixed Dose< 65 kg< 65 kg >> 65 kg 65 kg 40 mg40 mg 60 mg 60 mg q 12 hq 12 h
Fixed DoseFixed Dose
placebo placebo
q 12 hq 12 h
43 days
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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
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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
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Primary Endpoint : Day 43Death/MI/Urgent Revasc
Primary Endpoint : Day 43Death/MI/Urgent Revasc
00
22
44
66
88
1010
1212
1414
1616
1818
2020
00 44 88 1212 1616 2020 2424 2828 3232 3636 4040 4444
P=0.048RRR 12 %P=0.048P=0.048RRR 12 %RRR 12 %
UFHUFHUFH
ENOXENOXENOX
19.7 %19.7 %19.7 %
17.3 %17.3 %17.3 %
%%%
DaysDaysDays
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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
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Enoxaparin in DVT Prophylaxis
DOSAGE DURATION
in 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 SCinitiated 12h (3) preop
extended prophylaxis in 40 mg qd SC 3 weeks post dischargehip replacement
in patients undergoing 30 mg q12h SC average duration: 7 to 10 daysknee-replacement surg initiate 12-24h postop
in patients undergoing 40 mg qd SC average duration: 7 to 10 daysabdominal surgery initiate 2h preop
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Enoxaparin in Treatment ofin acute DVT with or without PE
DOSAGE DURATION
For 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
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Enoxaparin for UA and non-Q MI
DOSAGE DURATION
For 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
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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 hospitalization mean drug cost in U.S.* $155 $80 mean total cost of care $11,857 $12,620
mean duration of treatment 2.3 daysmutidose vial enoxaparin - 1 mg/kg at $0.38/mg
Circulation 1998;97:1702-1707
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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.