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Low-Molecular-Weight Heparinand

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)

• thrombin then acts on fibrinogen to generate fibrin clot


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


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


The Procoagulant State in Thrombolysis

The Procoagulant State in Thrombolysis

Amplification

Vascular Injury

Activation of PlateletsAnd Coagulation

Xa

Thrombin (IIa)


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


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


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


AT

Free Thrombin

Antithrombin and Free ThrombinAntithrombin and Free Thrombin

AT alone does not inactivate free-thrombin

ThrombinHF

S C


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


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


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


Mechanism of Action

• Summary– Catalyzes ATIII – Specific for fluid-phase thrombin– Prolongs aPTT by inactivating thrombin and

blocking Xa generation


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


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.


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


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



• 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



• 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


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


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


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


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


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


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


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


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


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


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


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


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


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.

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inactivating thrombin

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