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Understanding Anticoagulants

Alan P. Agins, Ph.D.President, PRN Associates

Continuing Medical Education, Tucson, AZ

The Good . . . and the Bad

Overview of Hemostasis

PlateletAggregation

PlateletActivation

Blood VesselConstriction

CoagulationCascade

Stable Hemostatic Plug

Fibrin formation

Reduced Bloodflow

Contact/ Tissue Factor

Primary hemostatic plug

Neural Mechanism

Blood Vessel Injury

ADP

Thrombin Thromboxane A2

Glycoproteins Ilb, IIIa

Endothelium

Fibrinogen

VWF

The Platelet Aggregation Step

ADP

Thrombin Thromboxane A2

Glycoproteins Ilb, IIIaExposed Collagen

Fibrinogen

Ca++ Ca++

Ca++ Ca++

Exposed Collagen

VWF

Tiss

ue

Fact

or

Collagen

Glycoproteins Ilb, IIIa

Exposed Collagen

VWF

AA TxA2cyclooxygenase

Collagen

Exposed Collagen

VWF

TxA2ADP

2

Collagen

Exposed Collagen

VWF

TxA2ADP

Exposed Phospholipid Surface site for coagulation cascade activity

The exciting, but really complicated biochemistry involving “factors” steps

IntrinsicPathway

ExtrinsicPathway

Tissue Factor

Contact Activation Pathway

Final Common Pathway

Intrinsic Extrinsic

Checks and Balances• Five mechanisms keep platelet activation and

the coagulation cascade in check.• Abnormalities can lead to an increased

tendency toward thrombosis:– Protein C– Antithrombin– Plasmin– Tissue factor pathway inhibitor– Prostacyclin

Hemostasis

PlateletsHemostatic plug

FibrinEndothelial cell

RBC

Causes of Thrombosis

• Composition of the blood (hypercoagulability)

• Quality of the vessel wall (endothelial cell injury)

• Nature of the blood flow (hemostasis)

Virchow's triad

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Arterial ThrombusUsually occur in association with pre-existing vascular disease, the most common of which is atherosclerosis ~ plaque rupture

Produce clinical manifestations by inducing tissue ischemia, either by obstructing flow or by embolizing into the distal microcirculation

May lead to MI, occlusive stroke or other ischemic events

Venous thrombusUsually in the lower limbs

- often asymptomaticCan produce acute symptoms if they cause inflammation of the vessel wall, obstruct flow, or embolize into the pulmonary circulation

Risks for ThrombosisCAD / plaque ruptureRecent SurgeryImmobilization causing stasis of blood. Travel ObesityMalignancy, especially adenocarcinoma Previous history of DVT or pulmonary embolus (PE) Pregnancy (up to 2 months postpartum) Fracture Heart failure (causes stasis) Oral contraceptive / Estrogen use

Indications For Anticoagulant Therapy

Arterial thromboembolic disease• Prosthetic heart valves• Mitral valve disease, especially with

atrial fibrillation• Congestive cardiomyopathies,

especially with AF• Atrial fibrillation• Mural cardiac thrombi• Transient ischemic attacks• Stroke in evolution

Indications For Anticoagulant Therapy

Venous thromboembolic disease

• Deep venous thrombosis (DVT)• Pulmonary embolism (PE)• Primary prophylaxis of DVT or PE

• Disseminated intravascular coagulation• Maintenance of patency of vascular

grafts, shunts, bypasses

Mucopolysaccharide: MW from 6,000 to 40,000 Da.

Average MW of commercial preps: 12,000 - 15,000.

Key structural unit of heparin is a unique pentasaccharide sequence

Heparin

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Heparin MechanismHeparin’s Limitations

Binds to plasma proteins – variable bioavailability

The Heparin : Antithrombin complex can only bind to and inhibit soluble thrombin – NOT firbrin-bound thrombin

Heparin’s Limitations Heparin - Adverse Effects• Hemorrhagic events

– Antidote = Protamine Sulfate• Non-hemorrhagic side-effects

– Elevation of serum aminotransferase levels• reported in as many as 80% of patients

receiving heparin• not associated with liver dysfunction• disappears after the drug is discontinued.

– Hyperkalemia• 5 to 10% of patients receiving heparin • Due to aldosterone suppression. • Can appear within a few days

• Rare side-effects- alopecia and osteoporosis

Heparin Monitoring• Activated partial thromboplastin time (aPTT) • Termed "partial" due to the absence of tissue

factor from the reaction mixture. • Indicator of the efficacy of both the "intrinsic"

(contact activation pathway) and the common coagulation pathways.

• Adequate therapeutic effect = aPTT ratio of 2.0-2.5 times of the baseline aPTT

• Monitor aPTT every 4 hours until therapeutic range has been achieved.

• Thereafter, monitor aPTT and platelet count daily.

Heparin Monitoring• Anti-Xa levels may be more reliable than aPTTs

for monitoring heparin in newborns and some children:

• At birth, aPTT is prolonged, reflecting the immaturity of the coagulation system.

• Children requiring heparin therapy frequently have underlying disorders that influence the baseline aPTT and therefore the response to heparin.

• Elevated factor VIII may cause subtherapeutic aPTT despite adequate anti-Xa level.

• In these children, aPTT may not correlate well with anti-Xa levels and thus checking both parameters may be helpful. In such conditions, anti-Xa should be used.

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Low Molecular Weight Heparin• LMWH: 4000-5000 (vs Heparin: 15,000+)

LMWHs inactivate Xa but have less effect on thrombin (some molecules not long enough)

– ratio of anti-Xa to anti-thrombin activity of 3:1– Do not prolong PTT unless dose high

• Advantages over heparin:– Easier to administer: sc, BID dosing– Dosage and anticoagulant effect easier to predict;

dose based on body weight– Lab monitoring not necessary in all patients– Less chance of inducing immune-mediated

thrombocytopenia – Smaller risk of osteoporosis in long-term use

Names of LMWHs• Enoxaparin (Lovenox)• Dalteparin (Fragmin) • Tinzaparin (Innohep)

– Differ chemically and pharmacokenetically but unsure if these differences are clinically significant

• Other products not yet approved here:– Fraxiparin, reviparin, nadroparin,

bemiparin, certoparin

LMWH Rx monitoring• Uncomplicated patients do not require

monitoring• Who may need to be?

– Newborns, children, pregnant women– Conditions: obesity, renal insufficiency,

malignancy, myeloproliferative disorders– Pts with hemorrhagic complications or with

initial therapy to confirm appropriate levels• Anti-Xa for monitoring

Why do we need newer Anticoagulants?• UFH and LMWHs are inconvenient for

the outpatient setting (IV or sq only)

• UFH and LMWHs can cause HIT:– Risk 0.2% with LMWH vs. 2.6 % with UFH– Pts with HIT still need to be anticoagulated

Categories of New Drugs

–Factor Xa inhibitors:• fondaparinux, idraparinux

–Direct Thrombin Inhibitors:• hirudin, lepirudin, desirudin,

bivalirudin, argatroban, ximelagatran

–Heparinoids:• Danaparoid (discontinued)

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Factor Xa inhibitors• Fondaparinux (Arixtra)

– Synthetic polysaccharide: – The drug is the unique pentasaccharide sequence that

UFH and LMWH use to bind to AT

Too short to inactivate thrombin (much like LMWH); need >18 saccharide units to inactivate thrombin

– Reacts with strong affinity to AT (reversible) →Induces conformational change in AT →Increased ability to inactivate Xa

Fondaparinux (Arixtra)

IIaII

Fibrinogen Fibrin clot

Extrinsic pathway

Intrinsicpathway

ATIII XaATIII ATIII

Fondaparinux

Xa

Antithrombin

IIAPlatelets

Fondaparinux– Does not interact with plasma proteins,

platelets, or platelet factor IV = useful in HIT (although not yet formally approved)

– FDA approved in 2001 • Prevention of post op VTE (DVT and PE) in

orthopedic surgery– Hip fracture, hip replacement, knee replacement– Fondaparinux vs. enoxaparin in one study decreased

VTE in knee replacement from 12.5 to 27.8%• 2004/5 approval:

– VTE treatment if administered with warfarin– Anticoagulation in abdominal surgery

• Potential uses being studied: MI, PCI, UA

Fondaparinux• Drug monitoring:

• APTT and PT are insensitive • PT/INR may or may not be proportional to

the clinical safety or efficacy—more studies needed

• Anti-factor Xa assay –must be calibrated with fondaparinux

– Long half-life (17 hours) = qd dosing(LMWH = BID)

Idraparinux– Longer acting analogue (q week dosing)

currently being developed

Factor Xa inhibitors - Summary

• Alternative agent for LMWH for prophylaxis or initial treatment of venous thromboembolism

• Treatment of HIT• No true antidote although Factor VIIa

may be of benefit• Ongoing trials with Idraparinux

Comparison Parenteral Anticoagulants

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Direct Thrombin Inhibitors

• Two types – Bivalent DTIs (hirudin and analogs) – Univalent DTIs bind only to the active site

• Direct thrombin inhibitors block both circulating thrombin and clot-bound thrombin.

• There is no therapeutic drug monitoringwidely available for DTIs

• The ecarin clotting time, although not in general clinical use, would be the most appropriate monitoring test.

Direct Thrombin Inhibitors

IIa

ArgatrobanMelagatran

Heparin binding site

Catalyticsite

SubstrateRecognition

Site

IIa

IIa

Hirudins

Bivalent DTIs

• All bind in active site and exosite I• IV, IM, SC• Reversible: Bivalirudin• Irreversible: Lepirudin, Desirudin• Minor differences in structure • Approved for acute coronary syndrome ("unstable

angina")• Less suitable for long-term treatment

IIa

Ximelagatran– First oral direct thrombin inhibitor– Prodrug of melagatran– Discontinued (2006) due to Liver Toxicity

Argatroban– IV – Second agent (the first is lepirudin) to be indicated

for heparin-induced thrombocytopenia (HIT). – Hepatically eliminated and can be used in patients

with end-stage renal disease.

Univalent DTIsIIa

Advantages of direct thrombin inhibitors

No nonspecific binding to plasma proteins

Not neutralized by platelet factor 4 (PF4)

Ability to inactivate free and bound thrombin

Inhibits thrombin-mediated platelet activation

No formation of heparin-PF4 complexes

Predictable anticoagulant response

Retains activity in presence of platelet-rich thrombi

Completely inhibits fluid-phase and fibrin-bound thrombin

No activation of clotting cascade or release of binding proteins

No heparin-induced thrombocytopenia

Courtesy of R Mehran, MD.

Oral Anticoagulants

Warfarin

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WARFARINSerendipitous history“WARF” = Wisconsin Alumni Research Foundation

(the holder of original patent)Taken by six – seven million patients in United States

THERAPEUTIC USES:Prophylaxis and treatment of venous thrombosis

Treatment of atrial fibrillation with embolism

Prophylaxis & treatment of pulmonary embolism

Adjunctive therapy for coronary occlusion

Prophylaxis in patients with prosthetic valves

Warfarin

Synthesis of Non-

Functional Coagulation

Factors

Vitamin K

VIIIXXII

Warfarin: Mechanism of Action

Warfarin

• Racemic mixture of two active optical isomers -R & S forms

• Both isomers active, however S-warfarin has 5X the potency of the R-isomer and modulates the in vivo activity of warfarin.

• Each isomer is cleared by different cytochrome P450 pathways.

• CYP2C9 is the principle enzyme that metabolizes S-warfarin

• CYP1A2 & CYP3A4 metabolize the R-isomer.

Warfarin - Adverse Effects“narrow therapeutic index”

HemorrhageRisk of severe bleeding small (1-2%/yr) but definite Any benefit needs to outweigh this risk when warfarin is considered as a therapeutic measure.

Skin necrosisPurple toe syndrome / Cholesterol embolism TeratogenecityOsteoporosisAgranulocytosis, leukopenia, diarrhea,nausea, anorexia

Warfarin MonitoringProthrombin Time

• The time it takes plasma to clot after addition of tissue factor

• Measures the extrinsic pathway and final common pathway (factors II, V, VII, X and fibrinogen)

• An estimated 800 million PT/INR assays are performed annually worldwide

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Terms: PT ratio (PTR) = Patient’s PT

Control PTISI - International Sensitivity Index

(standard for thromboplastin reagent)

INR = PTRISInormal range for the INR is 0.8-1.2

Warfarin Monitoring Desired Therapeutic Range

2.0-3.02.5-3.5 (high risk patients)

Myocardial infarction

2.0-3.02.5-3.5

Heart valve replacementBioprosthetic valveMechanical valve

2.0-3.0Mitral valve stenosis

2.0-3.0Atrial fibrillation

2.0-3.0Treatment of venous thromboembolism

2.0-3.0Prophylaxis of venous thromboembolism

INRIndication

Coagulation factors t1/2 vary from 6 – 72 hoursT1/2 of warfarin ranges from 1- 2.5 days

1st INR – 2 to 3 days – then daily until therapeutic for at least 2 consecutive days

Followed by - INR 2-3 times weekly for 1 – 2 weeks

Gradually reduce frequency to q4weeks (if stable)

Remember Changes made in Warfarin dose are not completely reflected in the INR until day 3 or 4

Timing of INR Monitoring Genetic Variability Vitamin K epoxide reductase

• Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) gene explain 30% of the dose variation between patients

• The Good: Polymorphisms lead to a more rapid achievement of a therapeutic INR

• The Not-so-Good: Shorter time to reach an INR > 4, which is associated with bleeding

• African-Americans are relatively less sensitive to warfarin

• Asian Americans are more sensitive

Genetic polymorphism of CYP2C9 may play a role in the interpatient variability of response to warfarin and predisposition to drug interactions.

Polymorphism of CYP2C9 exists in approx 10% of Caucasians (very rare in African American or Asian populations)

CYP2C9 polymorphisms do not influence time to reach effective INR (as opposed to VKORC1) but do shorten the time to INR >4

Genetic VariabilityCytochrome P450

Warfarin InteractionAlter metabolic clearance

Reduce absorption from the intestine

Inhibit synthesis of vitamin K-dependent coagulation factors

Increase metabolic clearance of vitamin K-dependent coagulation factor

Interfere with other pathways of hemostasis

Unknown mechanisms

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Agents that may reduce the effectiveness of oral anticoagulants – Increase risk of Thrombosis

Drugs / Lifestyle / Dietary Interaction

Reduce Absorption– Bile Acid Resins

Direct Antagonism– Vitamin K (dietary)

Independent Risk Factors– Oral contraceptives– Estrogen / SERMs

Increase Metabolic Clearance

– Carbamazepine– Rifampin– Phenytoin – St John’s wort– Cigarette smoking– Cruciferous

vegetables

Increase hemorrhage risk by inhibiting metabolic clearance of warfarin (increase INR)CYP 1A, 2C, 3A

OmeprazoleAmiodaroneKetoconazoleItraconazoleFluconazoleMetronidazoleCimetidine

Erythromycin Clarithromycin FluoroquinolonesProtease InhibitorsGrapefruit juice

Many others

Drugs / Lifestyle / Dietary Interaction

Increase hemorrhage risk by other mechanisms(pharmodynamic, pharmacokinetic, multiple pathways, etc)

• Antiplatelet Drugs• Botanical supplement affecting platelets

• Ginger, ginkgo, garlic, feverfew, St John’s wort• Glucosamine / chondroitin supplements (increases INR)• Alcohol • Some cephalosporin and sulfa antibiotics• COX-2 inhibitors• Valproate• Many others

Drugs / Lifestyle / Dietary Interaction Risks Related to Anticoagulants

• Warfarin has a narrow therapeutic index• Between 1993 & 2006 ~ 9,766 reports of bleeding

complications related to warfarin therapy.– 86% of these were considered serious / 10% were fatal.

• In April 2006, Warfarin ranked ninth in the list of drugs with the most reported adverse events (4,861 cases).

• In October 2006, a black box warning of the risk of bleeding was added to the package inserts for proprietary and generic warfarin products in the U.S.

Education is the key to keeping patients safe

– Proper dosing– Compliance – Potential for interactions with other drugs,

foods, lifestyle, etc– Need for routine bloodwork– Plan for handling bleeding

• Minor• Major

Antiplatelet Drugs

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CollagenVWF

AA TxA2cyclooxygenase

Clopidogrel Ticlopidine

ReoProAggrestatIntegralin

Aspirin

ADP receptor Aspirin

DipyradimoleCa++

Ca++

Endothelium

Why Low Dose ASA?

AA TxA2cyclooxygenase

AA PGI2cyclooxygenase

X

X

TxA2 (Thromboxane)Increases calcium flux• Adhesion • Aggregation• Vasoconstriction

PGI2 (Prostacyclin) Increases cAMP• Prevents Adhesion• Prevents Aggregation • Vasodilation

Endothelium

Why Low Dose ASA?

AA TxA2cyclooxygenase

AA PGI2cyclooxygenase

X

X

No nucleus

No new protein synthesis (ie., cyclooxygenase) for

life of platelet

Nucleated CellsProduce mRNASynthesize new cyclooxygenaseContinue to make beneficial PGI2

TxA2 (Thromboxane)Increases calcium flux• Adhesion • Aggregation• Vasoconstriction

PGI2 (Prostacyclin) Increases cAMP• Prevents Adhesion• Prevents Aggregation • Vasodilation

Aspirin

– Antiagregation occurs within 1hr– Side Effects: Allergy, GI discomfort, GI bleed– OTC, easy to crush, inexpensive, small tablet,

enteric coated available to decrease stomach upset

– Remember: Aspirin’s effect on cyclooxygenase is irreversible. It will take at least 7 - 8 days after stopping therapy to completely restore platelet function

CollagenVWF

AA TxA2cyclooxygenase

Clopidogrel Ticlopidine

ADP receptor

Ca++

Ca++

Clopidogrel– Takes 2 to 3days; maximum inhibition between 4

and 6 days– Oral loading dose of 300mg results in faster

platelet inhibition (2-3hrs)– Alternative in ASA allergy / aspirin resistance– Fewer gastrointestinal hemorrhages than aspirin,

but more diarrhea and rash– Once daily, prescription required, expensive– Drug requires conversion to active metabolite

(CYP 3A4)– Like ASA, effect is irreversible. It will take at least

7 - 8 days after stopping therapy to completely restore platelet function

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Ticlopidine

– MOA not entirely known (similar to clopidogrel) – Takes 2 to 3days; maximum inhibition between

4 and 6 days– many adverse events (diarrhea 20%, other GI

sx, rash, neutropenia is rare 1% but severe –occurs in first 2-3mos, also thrombocytopenic purpura)

– Due to serious and common side effects, and the fact that it’s not much better than alternatives, it’s now rarely used

Antiplatelet Therapy: Common Oral Agents

ThienopyridineThienopyridineSalicylateClass

1% alone2-6% w/ ASA

1- 4% alone3-5% w/ ASA

2-3%Major Bleeding Risk (%)

250 mg twice daily75 mg daily75-325 mg dailyMaintenance Dose

Active DrugPro-DrugActive DrugFormulation

TiclopidineClopidogrelAcetylsalicylic acid (ASA)

CollagenVWF

AA TxA2cyclooxygenase

ADP receptor

DipyradimoleCa++

Ca++

Dipyridamole + Aspirin

– Increases cAMP = decreased calcium entry = decreases platelet activation

– 38% risk reduction for combo, better than either agent alone

– Headache is a common SE; similar bleeding to ASA

– Twice daily, capsule may be opened up & tablet crushed but granules must not be crushed – issues with tubes, ASA allergy