Transcript Document
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
Tissue trauma
Intrinsic Pathway
Blood trauma/ contact with collagen
Activation of factor
XII, IX, VIII
Leakage of Tissue Factor
Ca+2, factor VII
X
Xa
X
Ca+2
Ca+2
Prothrombin activator
Prothrombin
activator
Ca+2
Prothrombin
(factor II)
Xa
Thrombin
Prothrombin
(factor II)
Thrombin
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
Fibrin Monomers
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
Vitamin K reduced
Inactive factors II,
VII, IX, and X
Proteins S and C
Active factors II,
VII, IX, and X
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 KDEPENDENT PROTEINS
Factor II
Factor VII
72h
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
thromboembolism
2.0-3.0
Treatment of venous
thromboembolism
Atrial fibrillation
2.0-3.0
Mitral valve stenosis
2.0-3.0
Heart valve replacement
Bioprosthetic valve
Mechanical valve
2.0-3.0
2.5-3.5
Myocardial infarction
2.0-3.0
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%
% Responders
72%
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
Followup=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
person-years
2.6
7.2
Bleeding requiring
hospitalization
0.9
0.4
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
Cumulative Rate of Events (%)
Placebo
0.20
48%
Low-intensity
warfarin
0.15
0.10
0.05
0.00
0
1
2
3
Years of Follow-up
4
NEJM 2003; 348 (15): 1425-1434