Download BLOOD COAGULATION

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