Anticoagulant Therapy.ppt

8/11/2019 Anticoagulant Therapy.ppt

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Anticoagulant Therapy

Stephen Larsen

Institute of Haematology

RPAH


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Definition of Anticoagulation

Therapeutic interference ("blood-thinning")

with the clotting mechanism of the blood

to prevent or treat thrombosis and

embolism.


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Overview

Indications

A basic case study

Heparin/heparin like drugs and their

complications

Warfarin

New anticoagulant drugs


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Indications of Anticoagulant

Therapy Treatment and Prevention of Deep Venous

Thrombosis

Pulmonary Emboli Prevention of stroke in patients with atrial

fibrillation, artificial heart valves, cardiacthrombus.

Ischaemic heart disease During procedures such as cardiac

catheterisation and apheresis.


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A basic case study

51 year old man

Has severe osteoarthritis

Required surgery on his right knee

Underwent a total knee replacement

4 days after surgery complained of anincrease in pain and swelling in the calf

of the right leg


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A doppler ultrasound demonstrated a

thrombosis in the deep veins of the calf

extending up to the popliteal vein.

Was started on 12 hourly injections of the lowmolecular weight heparin clexane given as

subcutaneous injection

Simultaneously started on an oral tablet,

warfarin, 5mg once per day.


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Had daily blood tests to monitor the INR.

After 5 days, the INR had gone up to 2.2. The

clexane was stopped and he was discharged

from hospital to continue on warfarin 5mgdaily.

He underwent INR testing every two weeks.

The warfarin was stopped after 3 months. He

had no recurrence.


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Pertinent Questions from this

case How do heparin drugs work?

How does warfarin work?

Why start both clexane and warfarin?

What is an INR and how is heparin

monitored?

What are the risks of both of these

types of drugs?


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Standard Heparin

Heterogenous mixture of polysaccharidechains

MW 3k to 30k Active in vitro and in vivo

Administration - parenteral- Do not inject IM -only IV or deep s.c.

Half-life 1 - 2 hrs - monitor APTT Adverse effect - haemorrhage - antidote -

protamine sulphate


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Enhances

Antithrombin Activity


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Heparin mechanism of action

Heparin

Antithrombin IIIThrombin


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Monitoring Heparin

Activated Partial Thromboplastin Time

(APTT)

Normal range: 25-40 seconds

Therapeutic Range: 55-70 seconds

Timing

4-6 hours after commencing infusion

4-6 hours after changing dosing regimen


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Low Molecular Weight Heparin

Changed management of venousthromboembolism

Standard (Unfractionated) heparin 3k to30k

LMWH contains polysaccharide chains

MW 5k Enriched with short chains with higheranti-Xa:IIa ratio


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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

Less than half of the chains of LMWH are

long enough


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Complications of Heparin

Haemorrhage

Heparin-induced thrombocytopaenia

(HIT)

Osteoporosis (long-term only)


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Heparin-Induced

Thrombocytopaenia Most significant adverse effect of

heparin after haemorrhage

Most common drug-inducedthrombocytopenia

A large number of patients receive

heparin in the hospital environment.


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Non-immune heparin-associated

thrombocytopaenia (HIT Type I) Benign

Up to 10% patients on heparin

Rapid decline in platelet count withinfirst 2 days of heparin administration

Platelet count >100 000/ul

Returns to normal within 5 days despitecontinued heparin use (or within 2 daysif heparin is stopped).


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Heparin-induced

thrombocytopaenia: HIT type 2 Potentially catastrophic thrombosis (Heparin-

induced thrombocytopenia and thrombosis)

8% of patients on heparin develop antibodywithout becoming thrombocytopenic

1-5% patients on heparin developthrombocytopaenia

Of those with thrombocytopaenia, 30%develop venous and/or arterial thrombosis

Bleeding uncommon


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Trreatment of HIT

Discontinue all heparin

If need to continue anti-coagulation, use

danaparoid (orgaran).

Avoid platelet transfusions

Thrombosis: use danaparoid or

thrombin inhibitor


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Vitamin K

Synthesis ofFunctional

CoagulationFactors

VII

IX

X

II

Vitamin K-Dependent Clotting

Factors


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Warfarin

Synthesis ofNon

FunctionalCoagulation

Factors

Antagonismof

Vitamin K

Warfarin Mechanism of Action

Vitamin K

VII

IX

X

II


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Enhances

Antithrombin Activity

Warfarin


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Warfarin: Major Adverse Effect

Haemorrhage Factors that may influence bleeding

risk:

Intensity of anticoagulation Concomitant clinical disorders

Concomitant use of other medications

Quality of management


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Warfarin-induced Skin Necrosis


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Prothrombin Time (PT)

Historically, a most reliable and relied uponclinical test

However:

Proliferation of thromboplastin reagentswith widely varying sensitivities to reducedlevels of vitamin K-dependent clottingfactors has occurred

Problem addressed by use of INR(International Normalised Ratio)


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INR: International Normalised

Ratio A mathematical correction (of the PT ratio)

for differences in the sensitivity of

thromboplastin reagents INR is the PT ratio one would have obtained if

the reference thromboplastin had been used

Allows for comparison of results between labs

and standardises reporting of the prothrombintime


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( )

Patients PT in Seconds

Mean Normal PT in Seconds

INR =ISI

INR = International Normalised Ratio

ISI = International Sensitivity Index

INR Equation

Target INR

DVT, PE, Atrial Fibrillation: 2-3

Artificial Cardiac Valve: 3-3.5


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Changing over from Heparin to

Warfarin May begin concomitantly with heparin therapy

Heparin should be continued for a minimum

of four days Time to peak antithrombotic effect of

warfarin is delayed 96 hours (despite INR)

When INR reaches desired therapeutic

range, discontinue heparin (after a minimum

of four days)


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Relative Contraindications to

Warfarin Therapy Pregnancy

Situations where the risk of hemorrhage

is greater than the potential clinicalbenefits of therapy

Uncontrolled alcohol/drug abuse

Unsupervised dementia/psychosis


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Signs of Warfarin Overdosage

Any unusual bleeding:

Blood in stools or urine

Excessive menstrual bleeding

Bruising

Excessive nose bleeds/bleeding gums

Persistent oozing from superficial injuries Bleeding from tumor, ulcer, or other lesion


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Reversing action of warfarin

Plasma

Rapid but short-lasting

Vitamin K Not rapid, but lasts 1-2 weeks. Do not use

if wishing to restart warfarin within next

week.


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New Anticoagulation Drugs

Direct Thrombin Inhibitors

Ximelagatran, hirudin, bivalirudin, and

argatroban Synthetic pentasaccharide

Acivated Protein C

Tissue Factor Pathway Inhibitor (TFPI)


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Why do we need new

anticoagulation drugs? Heparin-induced thrombocytopenia

Heparin prophylaxis is imperfect

Heparin-associated osteoporosis Warfarin takes several days for its effect

Warfarin is not as effective in some situations

e.g antiphospholipid syndrome Warfarin interacts with many other drugs

Warfarin is dangerous if not monitored


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Synthetic Pentasaccharide

E.g Fonaparinux

Synthetic, single molecular entity

Targets Factor Xa Does not cause thrombocytopenia

Shown promise in DVT prevention

during orthopedic procedures. Also being examined in ischaemic heart

disease


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Ximelagatran

Promising oral direct thrombin inhibitor

Converted to the active form melagatran

in vivo

No dosing problems

No monitoring needed.

Recent atrial fibrillation study showed it

to possibly be superior to warfarin.


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Enhances

Antithrombin ActivityXimelagatran


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Conclusion

Anticoagulant therapy is use extensively.

Current mainstays of treatment are heparin or

heparin-like drugs and oral warfarin. Both have problems but when monitored

closely are generally safe.

New anticoagulation drugs are arriving and in

particular ximelagatran may revolutionise oral

anticoagulation therapy

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Anticoagulant Therapy.ppt