LowMolecularWeight Heparin and Unfractionated Heparin

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Low-Molecular-Weight HeparinandUnfractionated
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 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
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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
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The Procoagulant State in Thrombolysis
Vascular Injury
Activation of Platelets And Coagulation
Amplification
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-XaIIa 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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Interaction of Heparin Co-Factors with Thrombin
AT is an effective antithrombin but HC II is a
very weak antithrombin
AT
There are two heparin-cofactors, Antithrombin
(AT) and Heparin Co-factor II (HC II).
HC II
- - - -
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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
- - - -
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Antithrombin and Free Thrombin
AT alone does not inactivate free-thrombin
Free Thrombin
AT
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Inactivation of Thrombin byHeparin-AT Complexes
Heparin
AT
Heparin binds to antithrombin and increases the
rate of thrombin inactivation
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Effect of Antithrombin on Fibrin-Bound Thrombin
The rate at which AT inactivates fibrin-bound
thrombin is reduced 50-fold
Fibrin-Bound Thrombin
AT
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Inactivation of Thrombin by Heparin-AT Complexes
Fibrin
Heparin
When thrombin binds to fibrin, it becomes
resistant to inactivation by heparin.
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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
• lt half the chains of LMWH are long enough

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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.
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Low-Molecular-Weight HeparinsAnti-Facotr Xa
Anti - Factor IIa Ratios

• Agent Trade XaIIa 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-rel
  ated 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 gt2.0 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
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 1997337447-452
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ESSENCE

• 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 plt.001
• Major bleeding30 d 6.5 7.0 NS
• Death alone14 d 2.2 2.3 NS30 d
  2.9 3.6 NS

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
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TIMI 11B - Study Design
Fixed Dose lt 65 kg gt 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
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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 plt0.03

Circulation 1999 1001593-1601
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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
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Difference Between Lovenox and Heparin

• Lovenox Heparin
• Half-life (hr) 4.5 dose-dependent
• Anti-XaIIa 141 11
• 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 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

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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

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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

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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 12,620mean duration of treatment
  2.3 days mutidose vial enoxaparin - 1 mg/kg at
  0.38/mg

Circulation 1998971702-1707
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References

• Low-molecular weight heparins.Weitz JI. N Eng J
  Med 1997337688-698.
• Biochemistry and pharmacology of low molecular
  weight heparin.Rosenberg RD. Semin Hematol
  199734(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 19953321330-1335.
• Use of LMWH in the treatment of venous
  thromboembolic disease.Litin SC, Heit JA, Mees
  KA, for the Thrombophilia Center
  Investigators.Mayo Clin Proc 199873545-551.