1. WARFARIN
AN OVERVIEW

2. HEMOSTASIS VASCULAR SPASM PLATELET PLUG BLOOD COAGULATION
GROWTH OF FIBROUS TISSUE IN CLOT

3. WHEN DOES BLOOD COAGULATE?
Procoagulants > Anticoagulants
Injury to blood vessel
Blood stasis

4. INITIATION OF BLOOD COAGULATION
Extrinsic Pathway
Intrinsic Pathway
Tissue trauma
Leakage of Tissue Factor
Blood trauma/ contact with collagen
Activation of factor XII, IX, VIII
Ca+2, factor VII
X Xa
X Xa
Ca+2
Ca+2
Prothrombin activator
Prothrombin
activator
Ca+2
Prothrombin Thrombin
(factor II)
Prothrombin Thrombin
(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)

5. BLOOD COAGULATION Thrombin Fibrin Monomers Fibrinogen Fibrin threads
Ca+2, factor XIII
Fibrin threads

6. 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

7. WARFARIN: MECHANISM OF ACTION
Vitamin K epoxide
WARFARIN
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

8. 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

9. 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

10. WHY TO MONITOR WARFARIN THERAPY?
Narrow therapeutic range
Can increase risk of bleeding

11. MONITORING OF WARFARIN THERAPY
Prothrombin time
PT ratio
INR (International Normalized Ratio)

12. 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

13. Thromboplastins are extracts from brain, lung or placenta of animals
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

14. INTERNATIONAL NORMALISED RATIO (INR)
INR = [PTpt] ISI
[PTRef]
PTpt – prothrombin time of patient
PTRef – prothrombin time of normal pooled sample
ISI – International Sensitivity Index

15. 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)

16. OPTIMAL THERAPEUTIC RANGE
Indication
INR
Prophylaxis of venous thromboembolism
Treatment of venous thromboembolism
Atrial fibrillation
Mitral valve stenosis
Heart valve replacement
Bioprosthetic valve
Mechanical valve
Myocardial infarction
(high risk patients)

17. FACTORS INFLUENCING DOSE RESPONSE
Inaccurate lab testing
Poor patient compliance
Concomitant medications
Levels of dietary vitamin K
Alcohol
Hepatic dysfunction
Fever

18. DURATION OF THERAPY
Venous thromboembolism: Minimum 3 months, usually 6 months
AMI: During initial 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

19. 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

20. SIDE EFFECTS Hemorrhage Skin necrosis Purple toe syndrome
Microembolization
Teratogenecity
Agranulocytosis, leukopenia, diarrhoea,
nausea, anorexia.

21. SWITCHOVER FROM ONE BRAND OF WARFARIN TO ANOTHER/ ACENOCOUMAROL
Check patient’s INR
Start with dose of 2 mg; increase dose slowly as required

22. COMPARISON WITH ACENOCOUMAROL

23. THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER WITH WARFARIN AS COMPARED TO ACENOCOUMAROL
72%
72%
70%
67%
68%
% Responders
66%
64%
Warfarin
Acenocoumarol
Thrombosis And Haemostasis 1994; 71(2):

24. RECENT TRIALS ON WARFARIN

25. There were no major bleeds in either groups
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):

26. 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
NEJM 2003; 348 (15):

27. Warfarin Reduced the Risk of Recurrent Venous Thromboembolism, Major Hemorrhage, or Death From Any Cause
0.25
P=0.02
Placebo
0.20
48% ) % ( s t n e v
Low-intensity E
0.15 f
warfarin o e t a R e v t i
0.10 a l u m u C
0.05
0.00 1 2 3 4
Years of Follow-up
NEJM 2003; 348 (15):