SANJAY

1. WARFARINWARFARIN
Sanjay Kumar KulchaniaSanjay Kumar Kulchania
(LECTURER)(LECTURER)
M.M.INSTITUTE OF MEDICALM.M.INSTITUTE OF MEDICAL
& NURSING SCIENCES& NURSING SCIENCES

2. HEMOSTASISHEMOSTASIS
 VASCULAR SPASMVASCULAR SPASM
 PLATELET PLUGPLATELET PLUG
 BLOOD COAGULATIONBLOOD COAGULATION
 GROWTH OF FIBROUS TISSUE IN CLOTGROWTH OF FIBROUS TISSUE IN CLOT

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

4. INITIATION OF BLOOD COAGULATIONINITIATION OF BLOOD COAGULATION
Extrinsic PathwayExtrinsic Pathway
Tissue traumaTissue trauma
Leakage of Tissue FactorLeakage of Tissue Factor
XX XaXa
Prothrombin activatorProthrombin activator
CaCa+2+2
,, factor VIIfactor VII
CaCa+2+2
ProthrombinProthrombin ThrombinThrombin
(factor II)(factor II)
CaCa+2+2
Intrinsic PathwayIntrinsic Pathway
Blood trauma/ contact with collagenBlood trauma/ contact with collagen
Activation of factorActivation of factor
XII, IX, VIIIXII, IX, VIII
XX XaXa
CaCa+2+2
ProthrombinProthrombin
activatoractivator
ProthrombinProthrombin ThrombinThrombin
(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)

5. BLOOD COAGULATIONBLOOD COAGULATION
ThrombinThrombin
FibrinogenFibrinogen Fibrin MonomersFibrin Monomers
Fibrin threadsFibrin threads
CaCa+2+2
, factor XIII, factor XIII

6. ANTICOAGULANTSANTICOAGULANTS
 Heparin and Low Molecular WeightHeparin and Low Molecular Weight
Heparins (Heparins (e.g. enoxaparin, dalteparin)e.g. enoxaparin, dalteparin)
 Coumarin DerivatvesCoumarin Derivatves e.g. Warfarin,e.g. Warfarin,
AcenocoumarolAcenocoumarol
 Indandione DerivatvesIndandione Derivatves e.g. Phenindione,e.g. Phenindione,
AnisindioneAnisindione
Three classes

7. WARFARIN: MECHANISM OF ACTIONWARFARIN: MECHANISM OF ACTION
Inactive factors II,
VII, IX, and X
Proteins S and C
Active factors II,
VII, IX, and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WARFARIN
Prevents the reduction of vitamin K, which is essential forPrevents the reduction of vitamin K, which is essential for
activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus

8. PLASMA HALF-LIVES OF VITAMIN K-PLASMA HALF-LIVES OF VITAMIN K-
DEPENDENT PROTEINSDEPENDENT PROTEINS
Factor IIFactor II 72h72h
Factor VIIFactor VII 6h6h
Factor IXFactor IX 24h24h
Factor XFactor X 36h36h
Peak anticoagulant effect may be delayed by 72 to 96 hoursPeak anticoagulant effect may be delayed by 72 to 96 hours

9. INDICATIONSINDICATIONS
 Prophylaxis and treatment of venousProphylaxis and treatment of venous
thromboembolismthromboembolism (deep vein thrombosis and(deep vein thrombosis and
pulmonary embolism)pulmonary embolism)
 Prophylaxis and treatment of Atrial fibrillationProphylaxis and treatment of Atrial fibrillation
 Valvular stenosisValvular stenosis
 Heart valve replacementHeart valve replacement
 Myocardial infarctionMyocardial infarction

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

11. MONITORING OF WARFARINMONITORING OF WARFARIN
THERAPYTHERAPY
 Prothrombin timeProthrombin time
 PT ratioPT ratio
 INR (International Normalized Ratio)INR (International Normalized Ratio)

12. PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
 Time required for blood to coagulate is called PTTime required for blood to coagulate is called PT
 Performed by adding a mixture of calcium andPerformed by adding a mixture of calcium and
thromboplastin to citrated plasmathromboplastin to citrated plasma
 As a control, a normal blood sample is testedAs a control, a normal blood sample is tested
continuouslycontinuously
 PT ratio (PTR) =PT ratio (PTR) = Patient’s PTPatient’s PT
Control PTControl PT

13. PROBLEMS WITH PT/PTRPROBLEMS WITH PT/PTR
 Thromboplastins are extracts from brain,Thromboplastins are extracts from brain,
lung or placenta of animalslung or placenta of animals
 Thromboplastins from variousThromboplastins from various
manufacturers differ in their sensitivity tomanufacturers differ in their sensitivity to
prolong PTprolong PT
 May result in erratic control ofMay result in erratic control of
anticoagulant therapyanticoagulant therapy

14. INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
INR = [PTINR = [PTptpt]] ISIISI
[PT[PTRefRef]]
PTPTptpt – prothrombin time of patient– prothrombin time of patient
PTPTRefRef – prothrombin time of normal pooled sample– prothrombin time of normal pooled sample
ISI – International Sensitivity IndexISI – International Sensitivity Index

15. OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Dosage to be individualized according to patient’sDosage to be individualized according to patient’s
INR response.INR response.
Use of large loading dose may lead to hemorrhageUse of large loading dose may lead to hemorrhage
and other complications.and other complications.
 Initial dose: 2-5 mg once dailyInitial dose: 2-5 mg once daily
 Maintenance dose: 2-10 mg once dailyMaintenance dose: 2-10 mg once daily
 Immediate anticoagulation required:Immediate anticoagulation required: Start heparinStart heparin
along with loading dose of warfarin 10 mg. Heparinalong with loading dose of warfarin 10 mg. Heparin
is usually discontinued after 4-5 days.is usually discontinued after 4-5 days. BeforeBefore
discontinuing, ensure INR is in therapeutic range for 2discontinuing, ensure INR is in therapeutic range for 2
consecutive daysconsecutive days
 Monitor daily until INR is in therapeutic range, then 3Monitor daily until INR is in therapeutic range, then 3
times weekly for 1-2 weeks, then less often (every 4times weekly for 1-2 weeks, then less often (every 4
to 6 weeks)to 6 weeks)

16. OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venousProphylaxis of venous
thromboembolismthromboembolism
2.0-3.02.0-3.0
Treatment of venousTreatment of venous
thromboembolismthromboembolism
2.0-3.02.0-3.0
Atrial fibrillationAtrial fibrillation 2.0-3.02.0-3.0
Mitral valve stenosisMitral valve stenosis 2.0-3.02.0-3.0
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
2.0-3.02.0-3.0
2.5-3.52.5-3.5
Myocardial infarctionMyocardial infarction 2.0-3.02.0-3.0
2.5-3.52.5-3.5 (high risk patients)(high risk patients)

17. FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
 Inaccurate lab testingInaccurate lab testing
 Poor patient compliancePoor patient compliance
 Concomitant medicationsConcomitant medications
 Levels of dietary vitamin KLevels of dietary vitamin K
 AlcoholAlcohol
 Hepatic dysfunctionHepatic dysfunction
 FeverFever

18. DURATION OF THERAPYDURATION OF THERAPY
 Venous thromboembolism: Minimum 3 months,Venous thromboembolism: Minimum 3 months,
usually 6 monthsusually 6 months
 AMI: During initial 10-14 days of hospitalizationAMI: During initial 10-14 days of hospitalization
or until patient is ambulatoryor until patient is ambulatory
 Mitral valve disease/Mechanical heart valves:Mitral valve disease/Mechanical heart valves:
LifelongLifelong
 Bioprosthetic heart valves: 3 monthsBioprosthetic heart valves: 3 months
 Atrial fibrillation: LifelongAtrial fibrillation: Lifelong
 Prevention of cerebral embolism: 3-6 monthsPrevention of cerebral embolism: 3-6 months

19. CONTARINDICATIONS ANDCONTARINDICATIONS AND
PRECAUTIONSPRECAUTIONS
 Hypersensitivity to warfarinHypersensitivity to warfarin
 Condition with risk of hemorrhageCondition with risk of hemorrhage
 Hemorrhagic tendencyHemorrhagic tendency
 Inadequate laboratory techniquesInadequate laboratory techniques
 Protein C & S deficiencyProtein C & S deficiency
 Vitamin K deficiencyVitamin K deficiency
 Intramuscular injectionsIntramuscular injections

20. SIDE EFFECTSSIDE EFFECTS
 HemorrhageHemorrhage
 Skin necrosisSkin necrosis
 Purple toe syndromePurple toe syndrome
 MicroembolizationMicroembolization
 TeratogenecityTeratogenecity
Agranulocytosis, leukopenia, diarrhoea,Agranulocytosis, leukopenia, diarrhoea,
nausea, anorexia.nausea, anorexia.

21. SWITCHOVER FROM ONE BRAND OFSWITCHOVER FROM ONE BRAND OF
WARFARIN TO ANOTHER/WARFARIN TO ANOTHER/
ACENOCOUMAROLACENOCOUMAROL
 Check patient’s INRCheck patient’s INR
 Start with dose of 2 mg; increase doseStart with dose of 2 mg; increase dose
slowly as requiredslowly as required

22. COMPARISON WITHCOMPARISON WITH
ACENOCOUMAROLACENOCOUMAROL

23. THE OVERALL ANTICOAGULATION QUALITYTHE OVERALL ANTICOAGULATION QUALITY
IS SIGNIFICANTLY BETTER WITH WARFARINIS SIGNIFICANTLY BETTER WITH WARFARIN
AS COMPARED TO ACENOCOUMAROLAS COMPARED TO ACENOCOUMAROL
72%
67%
64%
66%
68%
70%
72%
%Responders
Warfarin Acenocoumarol
Thrombosis And Haemostasis 1994; 71(2): 188-191

24. RECENT TRIALS ONRECENT TRIALS ON
WARFARINWARFARIN

25. ANTICOAGULATION FOR VTE PROVOKED BYANTICOAGULATION FOR VTE PROVOKED BY
TRANSIENT RISK FACTORS (SURGERY etc) SHOULDTRANSIENT RISK FACTORS (SURGERY etc) SHOULD
BE CONTINUED FOR 3 MONTHSBE CONTINUED FOR 3 MONTHS
GroupGroup Incidence (%) per yearIncidence (%) per year
Warfarin for 1 monthWarfarin for 1 month 6.8%6.8%
Warfarin for 3 monthsWarfarin for 3 months 3.2%3.2%
Follow-
up=11 mths
There were no major bleeds in either groups
J Thromb Haemost. 2004; 2(5): 743-749

26. THETHE PPREVENTION OFREVENTION OF RERECURRENTCURRENT VENVENOUSOUS
TTHROMBOEMBOLISM (PREVENT) TRIALHROMBOEMBOLISM (PREVENT) TRIAL
Long-term use of low-intensity warfarin, preventsLong-term use of low-intensity warfarin, prevents
venous thromboembolism without increasing the riskvenous thromboembolism without increasing the risk
of hemorrhageof hemorrhage
NEJM 2003; 348 (15): 1425-1434NEJM 2003; 348 (15): 1425-1434
INCIDENCE OF VTES IN THE TWO TREATMENT GROUPSINCIDENCE OF VTES IN THE TWO TREATMENT GROUPS
Drug Warfarin Placebo
Events per 100
person-years
2.6 7.2
Bleeding requiring
hospitalization
0.9 0.40.4
N= 508508
Target INRTarget INR
1.5-2.01.5-2.0

27. Warfarin Reduced the Risk of Recurrent Venous Thromboembolism,
Major Hemorrhage, or Death From Any Cause
0 1 2 3 4
Years of Follow-up
0.00
0.05
0.10
0.15
0.20
0.25
P=0.02
Placebo
Low-intensity
warfarin
CumulativeRateofEvents(%) 48%
NEJM 2003; 348 (15): 1425-1434NEJM 2003; 348 (15): 1425-1434