Enoxaparin

Enoxaparin training slides Dr. B. K. Iyer

Topics for discusssion today
Clotting
Clotting cascade
Diseases to know
Anticoagulants
Heparin
LMWH
Enoxaparin

Clotting Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin

Clotting- why must we know?
Vascular disease - leading cause of death like
Acute Myocardial Infarction (AMI – Heart Attack)
Cerebrovascular Accident (CVA – Stroke)
Pulmonary Embolism (PE)
Venous Thrombosis (DVT)
Stastically: 1 in 3 die from Vascular Disease Complications

Clotting phenomenon Haemostasis, vessel disruption Platelet adherence aggregation & release Thrombin generation and fibrin formation Thrombosis, endothelial injury External Internal

The Procoagulant State Vascular Injury Activation of Platelets And Coagulation Fibrin formation Xa Thrombin (IIa)

Actions of thrombin Activation of platelets THROMBIN Factor XIII -> XIIIa cross linked fibrin Fibrinogen -> Fibrin Prothrombin -> Thrombin Factor V -> Va Factor VIII -> VIIIa

Clotting cascade The details Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin

Clotting Cascade
Clotting begins with certain abnormalities of the blood or blood vessel, triggering a cascade of enzymatic reactions of clotting factors.
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

Clotting Cascade - extrinsic
The extrinsic pathway begins when trauma exposes a membrane protein called tissue factor [TF] which then attaches to factor VII.
Factor VII then gets activated to factor VIIa.
The TF-VIIa complex then activates factor X.
With the activation of factor Xa, the extrinsic pathway ends.

Clotting Cascade - intrinsic
The intrinsic pathway begins when collagen in the damaged wall is exposed to blood, triggering the activation of clotting factors.
One of the first factors to get activated is Factor XII
Activated factor XII [XIIa] then activates factor XI.
Factor XIa then activates factor IX.
Activated factor IXa then activates factor VIII and combines with factor VIIIa to form tenase complex.
Tenase complex activates factor X forming factor Xa, leading to end of intrinsic pathway and beginning of common pathway.

Clotting Cascade - common
Activated factor Xa combines with factor Va to form a complex which converts prothrombin [II] to thrombin [IIa].
Next, thrombin converts fibrinogen to fibrin, a mesh like web in which the platelets get trapped as do the RBCs.

Clotting Cascade Intrinsic Pathway (surface contact) aPTT PT Thrombin ( IIa ) Thrombin-Fibrin Clot XIIa XIa IXa Xa Heparin / LMWH (AT-III dependent) Hirudin/Hirulog (direct antithrombin) Extrinsic Pathway (tissue factor) VIIa

Clotting Cascade

Clotting Cascade XIIa XIa IXa Xa IIa Fibrinogen Fibrin Hirsh, J., MD, FCCP, et. al., Heparin and Low Molecular Weight Heparin, Chest , 2001 ; 119, 64S-94S AT/LMWH Complex

Diseases To know with relation to LMWH usage Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin

The veins

Deep vein thrombosis
Annual incidence of venous thromboembolism (VTE) is 1/1000 and DVT accounts for over one half of VTE
The other half is PE
Carefully evaluated, up to 80% of patients with VTE have one or more risk factors
Majority of lower extremity DVT arise from calf veins but ~20% begin in proximal veins
About 20% of calf-limited DVTs will propagate proximally.

Pulmonary embolism [PE]
Blockage of the pulmonary artery or one of its branches,
Usually occurs when a deep vein thrombus (blood clot from a vein) becomes dislodged from its site of formation and travels to the arterial blood supply of one of the lungs.

Pulmonary embolism [PE]
Common symptoms include difficult breathing, chest pain on inspiration, and palpitations.
Clinical signs include low blood oxygen saturation (hypoxia), rapid breathing (tachypnea), and rapid heart rate (tachycardia).
Severe cases of untreated PE can lead to collapse, circulatory instability & sudden death

Anti coagulants What? Why? Where? Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin

Drugs in coagulation disorders Heparin Unfractionated Heparin Low molecular weight Heparin warfarin Direct Thrombin inhibitor Streptokinase Aspirin Clopidogrel Abiciximab Antiplatelets Thrombolytics Anticoagulants Drugs used in Coagulation disorders Hirudin Argotraban

Drugs in coagulation disorders Thrombogenesis Vascular injury Platelet adherence and activation Thrombin generation and fibrin formation Plasma generation and fibrinolysis Therapy Reduce risk factors Platelet inhibitors Anticoagulants Fibrinolytics

Ideal Anticoagulant
Administered orally, fixed oral dose daily
Highly effective in reducing venous thromboembolism
Predictable dose response and kinetics
Low rate of bleeding events
No routine coagulation monitoring required
Wide therapeutic window
No dose adjustment required
Little interaction with food or other drugs
Low, nonspecific plasma protein binding
Inhibition of both free and clot-bound coagulation factors

Heparin And allied products Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin

History of heparin
Heparin-discovered n 1916 by Jay McLean and William Howell (Johns Hopkins University)
Sulfated form perfected and deemed safe for use as an anticoagulant by Connaught Medical Labs (University of Toronto) - 1937
Heparin, sulfated form Hirsh, J., MD, FCCP, et. al., Heparin and Low Molecular Weight Heparin, Chest , 2001 ; 119, 64S-94S Garrett R., Grisham, C., Biochemistry With a Human Focus, Thompson Learning, 1997, p. 238

Heparin - structure
Glycosaminoglycan – polysaccharide polymer consisting of 2 types of monosaccharide that together provide the disaccharide building blocks for the heparin polymer:
a uronic acid residue and
a glucosamine residue

Heparin - types
Obtained from porcine intestine and bovine lung tissues.
This is processed by chemical or enzymatic degradation to provide LMWH that are chemically distinct products.
Anticoagulant efficacy and pharmacologic properties vary with the size of the molecules.
Parenteral agents:
administered either IV or SC.

Heparin - differences
UFH (mw 3k - 30k) is a heterogeneous mixture of polysacchride chains (glycosaminoglycans)
LMWH (mw 5k) is
obtained by alkaline degradation of heparin benzyl ester
enriched with short chains to better the anti-Xa:IIa ratio

Heparin - molecular Heterogeneity High Molecular Weight Medium Molecular Weight Small Molecular Weight Both functional and molecular heterogeneity is observed.

LMWH manufacturing process Depolymerization inflicts other changes Heparin derived oligosaccharides < 2.5 kDa UFH 15 kDa Anti-Xa/IIa = 1.0 LMWH 4-6 kDa Anti-Xa/IIa = 2.5 - 7.5 Ultra LMWH 2-4 kDa Anti-Xa/IIa = 10 - 50 Pentasaccharide 1-7 kDa Anti-Xa/IIa = > 50

Heparin - differences due to heterogeneity
UFH binds to plasma proteins, platelets (platelet factor 4), macrophages, and endothelial cells.
Limits bioavailability and accounts for the highly variable anticoagulant response.
LMWHs have reduced binding to plasma proteins, platelets, and other cells.
As a result, LMWHs have a more predictable dose response.

Heparin - action similarity
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 by inactivating thrombin and blocking Xa generation

aPTT
Activated partial thromboplastin time (aPTT) is a commonly used test to monitor heparin therapy and is a performance indicator measuring the efficacy of both the "intrinsic" and the common coagulation pathways.
The prothrombin time (PT) measures the extrinsic pathway.
Values < 25 seconds or > 39 seconds are generally abnormal.

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 Xa Fluid Thrombin HEPARIN HEPARIN & HIRUDIN

UFH – a few things to remember
Will affect PTT- how much depends dosing and your reagent system
Easily monitored (accurately!) with the Anti-Xa method
Can be used in patients with renal failure
HAS an antidote (protamine sulfate)
THE BIG QUESTION Why Use LMWH vs. UFH?

Why Use LMWH vs. UFH?
LMWH more expensive drug but overall costs about the same
No monitoring in majority of patients - when given on a weight-adjusted basis, the LMWH anticoagulant response is predictable and reproducible
Higher bioavailability - 90% vs 30%
Subcutaneous vs. IV
Outpatient vs. inpatient
Lower incidence of HIT

More predictable anticoagulant response needing little or no laboratory monitoring
Unfractionated heparin is mixture of large and small heparin fractions
Unfractionated heparin metabolism
Removes larger biologically inactive fractions quickly
Leaves behind smaller active fractions removed more slowly
LMWH = uniform size
LMWH = metabolized at a slower rate
Longer half-life - 4 to 6 hours vs 0.5 to 1 hour and renal (slower) vs hepatic clearance

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

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
Lower incidence of bone loss
Safe for use during pregnancy
More practical for long term use

LMWHs - clinical advantages
Greater bioavailability
100% versus 30% for heparin
Longer duration of action
slower clearance [ but can be a problem in renal dysfunction];
Less bleeding
↓ risk of heparin induced thrombocytopenia
↓ risk of osteoporosis

Differential inhibitory activity against factor Xa & IIa activity AT Unfractionated Heparin AT LMWH
By binding to AT, most UFH 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.
Thrombin (IIa) H F S C Thrombin (IIa) H F S C

LMWH The different ones

LMWH properties - differences

LMWHs - currently developed
Enoxaparin
(Aventis, France)
Dalteparin
(Pfizer, USA)
Tinzaparin
(Leo, Denmark)
Parnaparin
(Opocrin, Italy)
Each LMWH product has a specific molecular weight distribution.
This determines its anticoagulant activity and duration of action.

LMWHs: FDA Approvals X X UA X Total knee replacement X X X Total hip replacement X X X General surgery Prophylaxis in: X X Treatment DVT/PE X DVT-OPT Tinzaparin Enoxaparin Dalteparin Ardeparin Indications

LMWH Comparisons 4500 1.9: 1 Tinzaparin 3.5: 1 3.6: 1 3.8: 1 2.7: 1 1.9: 1 Xa: IIa ratio LMWHs have a relatively higher antifactor Xa, and lower antifactor II activity compared to unfractionated heparin. Potency of LMWH is reflected by the ratio of antifactor Xa to antifactor IIa activity (Xa:IIa ratio) 4653 Reviparin 4855 Nadroparin 4371 Enoxaparin 5819 Dalteparin 6000 Ardeparin 11,400 Heparin Mol. Wt. Product

LMWH - MOA

Differences in Mechanism of Action
Any heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT)
But, 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 Thrombin (IIa) H F S C AT LMWH Thrombin (IIa) H F S C

Xa: IIa ratio of heparin
Heparin produces its anticoagulant effects by binding to antithrombin III and inhibiting thrombogenesis primarily through inactivation of factors, IIa and Xa
The interaction with antithrombin III is mediated through a unique pentasaccharide molecule distributed randomly in the unfractionated heparin molecule.
The antithrombotic effects of unfractionated heparin require interaction with antithrombin III and factor Xa.
Binding of the unfractionated heparin antithrombin III complex to factor Xa causes a conformational change leading to inactivation of factor Xa.

Xa: IIa ratio of heparin
Unfractionated heparin can also bind to and inactivate factor II (thrombin).
However, this process requires simultaneous binding of the unfractionated heparin antithrombin III complex with thrombin, which necessitates that the unfractionated heparin be at least 18 saccharide units.
The longer saccharide units ([lt] 18 units) comprise less than 50% of the total fraction of low molecular weight heparins, so LMWHs have a relatively higher antifactor Xa, and lower antifactor II activity compared to unfractionated heparin.
Potency of LMWH is reflected by the ratio of antifactor Xa to antifactor IIa activity (Xa:IIa ratio).

LMWHs Structural Features
The molecular weight threshold under which anti-IIa activity is lost is 5400 daltons.

LMWH
Doesn’t change the APTT (much) – an increased APTT may signify an overdose of LMWH or some other influence on the APTT (platelet antibodies)
Difficult to reverse with protamine sulfate (antidote for UFH)
Cleared through the kidneys

LMWH administration
Subcutaneous injection
Once every 12 or 24 hours
Outpatient

LMWH Monitoring - When?
Unnecessary in majority of patients
Trough – right before next dose
May be useful in specific instances and patients that need monitoring are-
Pregnant
Pediatric
Renal insufficiency [ creatinine >2.0 mg/dl]
Prolonged therapy
Those at risk for bleeding
Obese patients with altered drug pK

LMWH - Who to monitor?
Patients with kidney problems (need to check creatinine clearance)
Patients that are obese or have a very low body weight
Children, burn patients

LWMH and PTT
“ LMWH fractions … have progressively less effect on the aPTT as they are reduced in molecular size, while still inhibiting activated factor X.
The aPTT activity of heparin reflects mainly its anti-factor IIa activity.” Hirsh J., Circulation 2001; 103:2994
AT Unfractionated Heparin AT LMWH Thrombin (IIa) H F S C Thrombin (IIa) H F S C

LMWH - How to monitor?
Unfractionated heparin has primarily antithrombin (factor IIa) activity that results in a linear increase in the PTT
Monitor UFH with PTT
Low molecular weight heparin has anti-Xa activity but PTT not sensitive enough to pick this up consistently, therefore need a more sensitive test
Monitoring LMWH with anti-Xa, is more appropriate, but not widely available. Samples should be drawn 4 hours after dosing.

Heparin induced thrombocytopenia
Mode of action – Immune
Heparin acts as a “cofactor” with PF4
Causes platelet
activation
aggregation
Rate of occurrence
Bovine - 15%
Porcine - 5%
Type I – HIT
Type II – HITT(with thrombosis)
Arterial thrombosis - 0.4%

Heparin induced thrombocytopenia
Begins 3 - 15 days after start of heparin
If patient exposed to drug before thrombocytopenia can occur within a few hours.
Platelet count returns 4 days after stopping heparin.
Treatment
Stop heparin immediately
Use other drugs for anticoagulation.

Enoxaparin Better value for money

Structure Average Molecular Weight: 4500 Da Distribution: <2000 Da 20% 2000 – 8000 Da 68% >8000 Da 18% Prescribing Information, Sanofi-Aventis, 2007

Enoxaparin
Enoxaparin is a low molecular weight heparin (LMWH) with anti-thrombotic properties
FDA Approval – December, 1998
Enoxaparin acts primarily on the coagulation factor Xa, and also, but to a lesser degree, on thrombin (factor IIa).
Centered at the convergence of the intrinsic and extrinsic coagulation pathways, factor Xa transforms prothrombin into thrombin.

Enoxaparin & Heparin - Differences Enoxaparin Heparin Half-life (hr) 4.5 dose-dependent Anti-Xa:IIa 14:1 1:1 Molecular wt (avg) 4,500 15,000 Time to peak activity 3-5 2-4 Dosing units mg IU

Enoxaparin - MOA AT LMWH Hirsh, J., MD, FCCP, et. al., Heparin and Low Molecular Weight Heparin, Chest , 2001 ; 119, 64S-94S Xa AT LMWH LMWH Xa AT LMWH Xa AT Xa

Enoxaparin - MOA Enoxaparin joins with antithrombin III (ATIII) to form a complex Enoxaparin thereby inhibits the subsequent step in the cascade, the generation of thrombin and other changes The enoxaparin-ATIII complex also prevents thrombin’s amplification effects on factor XIII, thus preventing stabilization of the clot.
Enoxaparin-ATIII complex then binds and inhibits factor Xa, thus -
prevents the Xa-Va complex, and subsequently
prevents the conversion of prothrombin to thrombin by the Xa-Va complex.

Pharmacology
Low molecular weight heparin with Antithrombotic properties
Binds to antithrombin (AT) and the LMWH-AT complex inactivates coagulation enzymes (specifically IIa, IXa, Xa, XIa, XIIa)
Enoxaparin
increases ratio of anti-Factor Xa to anti-Factor IIa.
Increases thrombin time up to 1.8 times that of control (slowing clotting time).

Pharmacodynamics / kinetics
Max. anti-Factor Xa and anti-Factor IIa (anti-thrombin) occur 3-5 hours post administration.
Peak activity concentration: 1.58 μg/mL
Primarily metabolized in Liver
By desulfation and depolymerization
t½: 4.5 hours
Eliminated in urine
Up to 20% of anti-Factor Xa recovered in urine after 24 hours
99Tc radio labeling method

Indications
Prophylaxis/Treatment of DVT
Presurgical / Postsurgical
PE
Inpatient Tx./ Outpatient Tx.

Indications
Therapy of AMI
Ischemic complications of Unstable Angina
STEMI (ST Segment Elevation Myocardial Infarction)

Enoxaparin in DVT Prophylaxis Average duration: 7 -10 days 30 mg q12h SC; initiate 12-24h postop In patients undergoing knee replacement surgery 3 weeks post discharge 40 mg qid SC Extended prophylaxis in hip replacement Average duration: 7 -10 days Upto 14 days 30 mg q12h SC; initiate 12-24h postop 40 mg qid SC; initiate 12h postop In patients undergoing hip replacement surgery average duration: 7-10 days 40 mg qid SC; initiate 2h postop In patients undergoing abdominal surgery DURATION DOSAGE

Enoxaparin - Therapy in acute DVT with or without PE continue enoxaparin for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (INR 2.0 to 3.0). 1 mg/kg q12h SC initiate warfarin sodium therapy when appropriate (usually within 72h of enoxaparin administration For patients who can be treated at home for acute DVT without PE average duration: 7 days 1.5 mg/kg qd SC or 1 mg/kg q12h SC at the same time every day. For hospitalized patients with acute DVT with or without PE DURATION DOSAGE

Enoxaparin - UA and non-Q MI minimum 2 days; usual duration of therapy: 2 to 8 days 1 mg/kg q12h SC with oral aspirin therapy (100 to 325 mg once daily) For the prevention of ischemic complications of unstable angina and non-Q-wave myocardial infarction (MI) when concurrently administered with aspirin DURATION DOSAGE

Pharmacological differences between LMWHs

Enoxaparin – ↓ in SMC proliferation

Pharmacokinetics of IV / SC

Administration
Must be given parenterally
IV and SC. Why?
Destroyed in GI Tract
IM administration causes hematoma
Supplied in Prefilled syringes and multi-dose vials

Contraindications
Active, major bleeding
Thrombocytopenia
Sensitivity to:
Heparin
Pork or pork products
Dose adjustment in hepatic or renal impairment

Adverse Reactions
Hemorrhage
Anemia
Thrombocytopenia
(decreased platelet count)
Diarrhea
Nausea
LD50 46.4 mg/kg
OD Treatment: Protamine Sulfate infusion

Enoxaparin Clinical trial outcomes

Clinical trial outcomes

ESSENCE Trial - Efficacy 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 Trial - Efficacy and Safety of Subcutaneous enoxaparin in non-Q-Wave Coronary Events Study Enoxaparin 1.0 mg/kg q 12 h subcutaneous UFH 5,000 U bolus + inf aPTT 55-85 sec Unstable Angina Non-Q Wave MI Acute Phase min 48h, max 8 Days 30 days Enox Hep Incidence of death, MI, angina 14 d 16.6% 19.8% p=.019 30 d 19.8% 23.3% p=.016 Minor bleeding 30 d 13.8% 8.8% p<.001 Major bleeding 30 d 6.5% 7.0% NS Death alone 14 d 2.2% 2.3% NS 30 d 2.9% 3.6% NS

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 > 65 kg 40 mg 60 mg q 12 h 43 days Fixed Dose placebo q 12 h

TIMI 11B - LMWH 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-Analysis - ESSENCE & 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 43 Death/MI/Urgent Revasc

Economic Assessment of LMWH vs UFH - results from the ESSENCE Trial
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 days mutidose vial enoxaparin - 1 mg/kg at $0.38/mg
Circulation 1998;97:1702-1707

Warfarin A brief understanding

Oral Anticoagulants
Warfarin (Coumadin  ) and its derivatives [phenprocoumon; acenocoumarol] have been used for over 50 years.
Prophylactic use:
Prevention of thrombotic disorders
Therapeutic use:
Treatment of established thrombus
Approx 50% of Atrial fibrillation patients receive warfarin

Heparin vs. warfarin

Warfarin: Structure
Warfarin is an Analogue of Vitamin K
interferes with vitamin-K dependent carboxylation of several coagulation factors including II, VII, IX, and X, as well as anticoagulant proteins C and S.
Full anticoagulant effect is delayed
Average daily dose 4-5mg.

Warfarin: MOA
International Normalized Ratio (INR) is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the analytical system used.
The result (in seconds) for a prothrombin time performed on a normal individual will vary depending on what type of analytical system it is performed.
This is due to the differences between different batches of manufacturer's tissue factor used in the reagent to perform the test.
The INR was devised to standardize the results.

Warfarin: Precautions in Use
A narrow therapeutic index (range between effective and toxic doses)
Non-linear pharmacokinetics
Small changes in dose can result in considerable changes in the anticoagulant response

Warfarin: Control of Dose
Response can vary greatly
Many factors affect the dose of warfarin:
Patient age
Nutrition
Dietary vitamin K
Alcohol use
Concomitant disease state
Anemia
Liver disease
Biliary obstruction
Concomitant drug use
Compliance

Warfarin: Drug Interactions
Drugs potentiate warfarin:
By causing vitamin K deficiency
by displacing warfarin from protein binding sites
by decreasing clotting factor synthesis
by suppressing or competing for microsomal enzymes
by having antiplatelet aggregating properties
Drugs inhibit warfarin:
by decreasing warfarin absorption
by enhancing warfarin metabolism

Enoxaparin

by BALASUBRAMANIAM IYER

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