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WARFARIN

AN OVERVIEW
HEMOSTASIS

 VASCULAR SPASM

 PLATELET PLUG

 BLOOD COAGULATION

 GROWTH OF FIBROUS TISSUE IN CLOT


WHEN DOES BLOOD COAGULATE?

 Procoagulants > Anticoagulants


 Injury to blood vessel
 Blood stasis
INITIATION OF BLOOD COAGULATION
Extrinsic Pathway Intrinsic Pathway
Tissue trauma Blood trauma/ contact with collagen

Leakage of Tissue Factor Activation of factor


Ca+2 , factor VII XII, IX, VIII

X Xa X Xa
Ca+2 Ca+2

Prothrombin activator
Prothrombin
Ca+2 activator
Prothrombin Thrombin Prothrombin Thrombin
(factor II) (factor II)

Activation of certain factors (VII, II, X and protein C and S) is essential for
coagulation. This activation requires vit K (reduced form)
BLOOD COAGULATION

Thrombin

Fibrinogen FibrinMonomers

Ca+2 , factor XIII

Fibrin threads
ANTICOAGULANTS
Three classes
 Heparin and Low Molecular Weight
Heparins (e.g. enoxaparin, dalteparin)
 Coumarin Derivatves e.g. Warfarin,
Acenocoumarol
 Indandione Derivatves e.g. Phenindione,
Anisindione
WARFARIN: MECHANISM OF ACTION

Vitamin K epoxide

WARFARIN

Vitamin K reduced

Inactive factors II, Active factors II,


VII, IX, and X VII, IX, and X
Proteins S and C Proteins S and C

Prevents the reduction of vitamin K, which is essential for


activation of certain factors
Has no effect on previously formed thrombus
PLASMA HALF-LIVES OF VITAMIN K-
DEPENDENT PROTEINS
Factor II 72h
Factor VII 6h
Factor IX 24h

Factor X 36h

Peak anticoagulant effect may be delayed by 72 to 96 hours


INDICATIONS

 Prophylaxis and treatment of venous


thromboembolism (deep vein thrombosis and
pulmonary embolism)
 Prophylaxis and treatment of Atrial fibrillation
 Valvular stenosis
 Heart valve replacement
 Myocardial infarction
WHY TO MONITOR WARFARIN THERAPY?

 Narrow therapeutic range


 Can increase risk of bleeding
MONITORING OF WARFARIN
THERAPY
 Prothrombin time
 PT ratio
 INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)

 Time required for blood to coagulate is called PT


 Performed by adding a mixture of calcium and
thromboplastin to citrated plasma
 As a control, a normal blood sample is tested
continuously
 PT ratio (PTR) = Patient’s PT
Control PT
PROBLEMS WITH PT/PTR

 Thromboplastins are extracts from brain,


lung or placenta of animals
 Thromboplastins from various
manufacturers differ in their sensitivity to
prolong PT
 May result in erratic control of
anticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)

INR = [PTpt ] ISI

[PTRef ]
PTpt – prothrombin time of patient
PTRef – prothrombin time of normal pooled sample
ISI – International Sensitivity Index
OPTIMIZING WARFARIN THERAPY
Dosage to be individualized according to patient’s INR
response.
Use of large loading dose may lead to hemorrhage and
other complications.
 Initial dose: 2-5 mg once daily
 Maintenance dose: 2-10 mg once daily
 Immediate anticoagulation required: Start heparin along
with loading dose of warfarin 10 mg. Heparin is usually
discontinued after 4-5 days. Before discontinuing, ensure INR
is in therapeutic range for 2 consecutive days
 Monitor daily until INR is in therapeutic range, then 3 times
weekly for 1-2 weeks, then less often (every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGE
Indication INR
Prophylaxis of venous 2.0-3.0
thromboembolism
Treatment of venous 2.0-3.0
thromboembolism
Atrial fibrillation 2.0-3.0
Mitral valve stenosis 2.0-3.0
Heart valve replacement
Bioprosthetic valve 2.0-3.0
Mechanical valve 2.5-3.5
Myocardial infarction 2.0-3.0
2.5-3.5 (high risk patients)
FACTORS INFLUENCING DOSE RESPONSE

 Inaccurate lab testing


 Poor patient compliance
 Concomitant medications
 Levels of dietary vitamin K
 Alcohol
 Hepatic dysfunction
 Fever
DURATION OF THERAPY

 Venous thromboembolism: Minimum 3 months,


usually 6 months
 AMI: During initial 10-14 days of hospitalization
or until patient is ambulatory
 Mitral valve disease/Mechanical heart valves:
Lifelong
 Bioprosthetic heart valves: 3 months
 Atrial fibrillation: Lifelong
 Prevention of cerebral embolism: 3-6 months
CONTARINDICATIONS AND
PRECAUTIONS
 Hypersensitivity to warfarin
 Condition with risk of hemorrhage
 Hemorrhagic tendency
 Inadequate laboratory techniques
 Protein C & S deficiency
 Vitamin K deficiency
 Intramuscular injections
SIDE EFFECTS

 Hemorrhage
 Skin necrosis
 Purple toe syndrome
 Microembolization
 Teratogenecity

Agranulocytosis, leukopenia, diarrhoea,


nausea, anorexia.
SWITCHOVER FROM ONE BRAND OF
WARFARIN TO ANOTHER/
ACENOCOUMAROL
 Check patient’s INR
 Start with dose of 2 mg; increase dose
slowly as required
COMPARISON WITH
ACENOCOUMAROL
THE OVERALL ANTICOAGULATION QUALITY
IS SIGNIFICANTLY BETTER WITH WARFARIN
AS COMPARED TO ACENOCOUMAROL

72%

72%
% Responders

70%
67%
68%

66%

64%
Warfarin Acenocoumarol

Thrombosis And Haemostasis 1994; 71(2): 188-191


RECENT TRIALS ON
WARFARIN
ANTICOAGULATION FOR VTE PROVOKED BY
TRANSIENT RISK FACTORS (SURGERY etc) SHOULD
BE CONTINUED FOR 3 MONTHS

Group Incidence (%) per year

Warfarin for 1 month 6.8%

Warfarin for 3 months 3.2%

There were no major bleeds in either groups


Follow-
up=11 mths

J Thromb Haemost. 2004; 2(5): 743-749


THE PREVENTION OF RECURRENT VENOUS
THROMBOEMBOLISM (PREVENT) TRIAL

Long-term use of low-intensity warfarin, prevents


venous thromboembolism without increasing the risk
of hemorrhage
INCIDENCE OF VTES IN THE TWO TREATMENT GROUPS
Drug Warfarin Placebo
Events per 100 2.6 7.2
person-years
Bleeding requiring 0.9 0.4
hospitalization

N= 508
Target INR
1.5-2.0
NEJM 2003; 348 (15): 1425-1434
Warfarin Reduced the Risk of Recurrent Venous Thromboembolism,
Major Hemorrhage, or Death From Any Cause

0.25
P=0.02
Placebo

0.20
Cumulative Rate of Events (%) 48%

0.15 Low-intensity
warfarin

0.10

0.05

0.00
0 1 2 3 4
Years of Follow-up
NEJM 2003; 348 (15): 1425-1434