This document discusses anticoagulation and anticoagulant medications. It begins by covering the physiology of coagulation and conditions involving hypercoagulability. It then describes various categories of antithrombotic drugs, focusing on anticoagulants including unfractionated heparin, low molecular weight heparins, vitamin K antagonists like warfarin, and newer anticoagulants. The mechanisms of action, indications, administration, monitoring, and complications of unfractionated heparin are discussed in detail using a case study as an example.

1. AnticoagulationAnticoagulation
Part 2 (Anticoagulants)Part 2 (Anticoagulants)
Monkez M Yousif MDMonkez M Yousif MD
Professor of Internal MedicineProfessor of Internal Medicine
20122012

2. ObjectivesObjectives
 Physiology of coagulationPhysiology of coagulation
 Thrombophilia (Hypercoagulation states)Thrombophilia (Hypercoagulation states)
 Venous thromboembolismVenous thromboembolism
 AnticoagulantsAnticoagulants
 Case studiesCase studies

3. Antithrombotic Drug CategoriesAntithrombotic Drug Categories
 Anticoagulant drugsAnticoagulant drugs::
– Heparin, low molecular weight heparinsHeparin, low molecular weight heparins
– Oral anticoagulants: warfarinOral anticoagulants: warfarin
 Fibrinolytic drugsFibrinolytic drugs:: streptokinase, tissuestreptokinase, tissue
plasminogen activatorplasminogen activator
 Anti-platelet drugsAnti-platelet drugs:: aspirin, clopidogrel,aspirin, clopidogrel,
AbciximabAbciximab

4. Definition of AnticoagulationDefinition of Anticoagulation
 Therapeutic interference ("blood-thinning")Therapeutic interference ("blood-thinning")
with the clotting mechanism of the blood towith the clotting mechanism of the blood to
prevent or treat thrombosis and embolism.prevent or treat thrombosis and embolism.

5. Indications of AnticoagulantIndications of Anticoagulant
TherapyTherapy
 Treatment and Prevention of DVTTreatment and Prevention of DVT
 Pulmonary EmbolismPulmonary Embolism
 Prevention of stroke in patients with AF, artificialPrevention of stroke in patients with AF, artificial
heart valves, cardiac thrombus.heart valves, cardiac thrombus.
 Acute coronary syndromes (NSTE MI)Acute coronary syndromes (NSTE MI)
 During procedures such as cardiac catheterisationDuring procedures such as cardiac catheterisation
and apheresis.and apheresis.

6. A basic case studyA basic case study
 51 year old man51 year old man
 Has severe osteoarthritisHas severe osteoarthritis
 Required surgery on his right kneeRequired surgery on his right knee
 Underwent a total knee replacementUnderwent a total knee replacement
 4 days after surgery complained of an4 days after surgery complained of an
increase in pain and swelling in the calf ofincrease in pain and swelling in the calf of
the right legthe right leg

7.  A doppler ultrasound demonstrated a thrombosisA doppler ultrasound demonstrated a thrombosis
in the deep veins of the calf extending up to thein the deep veins of the calf extending up to the
popliteal vein.popliteal vein.
 Was started on 12 hourly injections of the lowWas started on 12 hourly injections of the low
molecular weight heparin clexane given asmolecular weight heparin clexane given as
subcutaneous injectionsubcutaneous injection
 Simultaneously started on an oral tablet, warfarin,Simultaneously started on an oral tablet, warfarin,
5mg once per day.5mg once per day.

8.  Had daily blood tests to monitor the INR.Had daily blood tests to monitor the INR.
 After 5 days, the INR had gone up to 2.2. TheAfter 5 days, the INR had gone up to 2.2. The
clexane was stopped and he was discharged fromclexane was stopped and he was discharged from
hospital to continue on warfarin 5mg daily.hospital to continue on warfarin 5mg daily.
 He underwent INR testing every two weeks.He underwent INR testing every two weeks.
 The warfarin was stopped after 3 months. He hadThe warfarin was stopped after 3 months. He had
no recurrence.no recurrence.

9. Pertinent Questions from thisPertinent Questions from this
casecase
 How do heparin drugs work?How do heparin drugs work?
 How does warfarin work?How does warfarin work?
 Why start both clexane and warfarin?Why start both clexane and warfarin?
 What is an INR and how is heparinWhat is an INR and how is heparin
monitored?monitored?
 What are the risks of both of these types ofWhat are the risks of both of these types of
drugs?drugs?

10. Common Anticoagulant MedicationsCommon Anticoagulant Medications
 Unfractionated HeparinUnfractionated Heparin
 Low Molecular Weight Heparin (LMWH)Low Molecular Weight Heparin (LMWH)
 Vitamin K antagonists (warfarin)Vitamin K antagonists (warfarin)
 New anticoagulantsNew anticoagulants
Danaparoid (Orgaran)Danaparoid (Orgaran)
Hirudin (Thrombexx)Hirudin (Thrombexx)
PentasaccharidePentasaccharide
Fondaparinux (Arixtra)Fondaparinux (Arixtra)
Oral small-molecule direct thrombin inhibitorOral small-molecule direct thrombin inhibitor

11. TF VIIa
IX
Xa
X
IXa
II Va
IIa
VIIIa
FIBRINOGEN FIBRIN
AnticoagulantsAnticoagulants
PENTASAC*PENTASAC*
DANAPAROIDDANAPAROID
FONDAPARINAUX
HIRUDIN*HIRUDIN*
ORAL SMALL-ORAL SMALL-
MOLECULE DTIMOLECULE DTI ††
**
†
* Natural hirudin is not approved by the
FDA for any indication; recombinant
hirudin (lepirudin) is approved for the
treatment of thrombosis associated with
HIT. Pentasaccharide and the new oral
small-molecule direct thrombin
inhibitor do not have FDA approval for
any indication.
†
DTI=direct thrombin inhibitor
Warfarin UFH & LMWH

12. Anticoagulant action ofAnticoagulant action of
HEPARINHEPARIN
Anticoagulant action ofAnticoagulant action of
HEPARINHEPARIN
PentasaccharidePentasaccharide
sequence of heparinsequence of heparin
(present in UFH and(present in UFH and
LMWH) binds to ATLMWH) binds to AT
causingcausing
conformationalconformational
change at its reactivechange at its reactive
centre acceleratingcentre accelerating
1000-fold its1000-fold its
interaction withinteraction with
factor Xa.factor Xa.
LMWH
UFH

13. UNFRACTIONATED HEPARINUNFRACTIONATED HEPARIN

14. Unfractionated HeparinUnfractionated Heparin
 A highly sulfated glycosaminoglycanA highly sulfated glycosaminoglycan
 The average molecular weight of heparinThe average molecular weight of heparin
preparations is in the range of 12 kDa to 15preparations is in the range of 12 kDa to 15
kDakDa
 Heparin is a naturally occurringHeparin is a naturally occurring
anticoagulant produced by basophiles andanticoagulant produced by basophiles and
mast cells.mast cells.

15. Unfractionated HeparinUnfractionated Heparin
 Obtained from mast-cell rich tissues inObtained from mast-cell rich tissues in
animalsanimals
– just for curiosity: porcine intestinal mucosa orjust for curiosity: porcine intestinal mucosa or
bovine lungbovine lung
 Doses are expressed in units of activity,Doses are expressed in units of activity,

16. UFHUFH:: Mechanism of ActionMechanism of Action

17. Heparin: pharmacokineticsHeparin: pharmacokinetics
 Heparin is not absorbed through the GITHeparin is not absorbed through the GIT
mucosamucosa
 Given parenterallyGiven parenterally
 If given i.v , onset of action immediateIf given i.v , onset of action immediate
 If given subcutaneously, onset of actionIf given subcutaneously, onset of action
delayed by 1-2 hr and considerable variation indelayed by 1-2 hr and considerable variation in
bioavailability (macrophage destruction)bioavailability (macrophage destruction)
 Half life 1-2 hours.Half life 1-2 hours.

18. Heparin: pharmacokinetics (2)Heparin: pharmacokinetics (2)
 Mostly cleared and degraded by reticulo-Mostly cleared and degraded by reticulo-
endothelial system. Small amount unaltered inendothelial system. Small amount unaltered in
urineurine

19. Unfractionated Heparin:Unfractionated Heparin:
IndicationsIndications
 Acute coronary syndrome, e.g., NSTEMIAcute coronary syndrome, e.g., NSTEMI
 Atrial fibrillationAtrial fibrillation
 Deep-vein thrombosis and pulmonary embolismDeep-vein thrombosis and pulmonary embolism
 Cardiopulmonary bypass for heart surgery.Cardiopulmonary bypass for heart surgery.
 HemofiltrationHemofiltration
 Indwelling central or peripheral venous cathetersIndwelling central or peripheral venous catheters

20. Unfractionated Heparin:Unfractionated Heparin:
ContraindicationsContraindications
– Hypersensitivity to heparinHypersensitivity to heparin
– Severe thrombocytopeniaSevere thrombocytopenia
– HIT syndromeHIT syndrome
– Suspected intracranial hemorrhageSuspected intracranial hemorrhage
– Uncontrolled active bleedingUncontrolled active bleeding

21. Heparin: Administration and MonitoringHeparin: Administration and Monitoring
 Continuous vascular infusionContinuous vascular infusion standardstandard
when given in full dosewhen given in full dose
– BolusBolus injection followed byinjection followed by maintenancemaintenance
dose delivered by infusion pumpdose delivered by infusion pump
– Sometimes given bySometimes given by intermittent intravenousintermittent intravenous
injectioninjection
– Monitoring is essentialMonitoring is essential. Activated partial. Activated partial
thromboplastin time (thromboplastin time (aPTTaPTT) is used) is used

22. Heparin: Administration and Monitoring (2)Heparin: Administration and Monitoring (2)
 Subcutaneous administrationSubcutaneous administration used for long-termused for long-term
management if patient cannot take oralmanagement if patient cannot take oral
anticoagulantsanticoagulants
– Once a stable value of aPTT is obtained, no need toOnce a stable value of aPTT is obtained, no need to
continue laboratory monitoringcontinue laboratory monitoring
 Low doseLow dose subcutaneous heparinsubcutaneous heparin sometimes givensometimes given
to patients in the post-surgery period as prophylaxisto patients in the post-surgery period as prophylaxis
of deep vein thrombosis and thromboembolismof deep vein thrombosis and thromboembolism
– Laboratory monitoring not necessaryLaboratory monitoring not necessary

23. Monitoring HeparinMonitoring Heparin
 Activated Partial Thromboplastin TimeActivated Partial Thromboplastin Time
(APTT)(APTT)
 Normal range: 25-40 secondsNormal range: 25-40 seconds
 Therapeutic Range: 55-70 secondsTherapeutic Range: 55-70 seconds
 TimingTiming
– 4-6 hours after commencing infusion4-6 hours after commencing infusion
– 4-6 hours after changing dosing regimen4-6 hours after changing dosing regimen

24. Unfractionated HeparinUnfractionated Heparin
 DosingDosing
– Varies by indication: usual VTE treatment isVaries by indication: usual VTE treatment is
IV heparin 80 units/kg IV bolus with 18IV heparin 80 units/kg IV bolus with 18
units/kg/hr IV infusion with dose adjustmentunits/kg/hr IV infusion with dose adjustment
per aPTT after 6 hours.per aPTT after 6 hours.
– If administered intravenously bolus andIf administered intravenously bolus and
continuous infusion is made via programmablecontinuous infusion is made via programmable
infusion pump with double checks made byinfusion pump with double checks made by
two independent checkerstwo independent checkers
(provider/nurse/pharmacist)(provider/nurse/pharmacist)

25. Unfractionated HeparinUnfractionated Heparin
Drug & Herbal InteractionsDrug & Herbal Interactions
– Decreased effectDecreased effect
» Nitroglycerin (I.V.)Nitroglycerin (I.V.)
– Increased effectIncreased effect
» Herbs/Nutraceuticals: garlic, green tea, ginseng,Herbs/Nutraceuticals: garlic, green tea, ginseng,
ginkgo (additional antiplatelet activity)ginkgo (additional antiplatelet activity)
» Drugs: warfarin, thrombolytics, dextran, aspirin,Drugs: warfarin, thrombolytics, dextran, aspirin,
NSAIDS, dipyridamole, ticlopidine, clopidogrel,NSAIDS, dipyridamole, ticlopidine, clopidogrel,
GP IIb/IIIa antagonists, antihistamines,GP IIb/IIIa antagonists, antihistamines,
tetracycline, quinine, nicotine and digoxintetracycline, quinine, nicotine and digoxin

26. Complications of HeparinComplications of Heparin
 HemorrhageHemorrhage
 Heparin-induced thrombocytopeniaHeparin-induced thrombocytopenia (HIT)(HIT)
 Osteoporosis (long-term only)Osteoporosis (long-term only)
 Hyperkalemia (aldosterone suppression)Hyperkalemia (aldosterone suppression)
 Elevation of liver enzymesElevation of liver enzymes
 AlopeciaAlopecia

27. Heparin-InducedHeparin-Induced
ThrombocytopaeniaThrombocytopaenia
 Most significant adverse effect of heparinMost significant adverse effect of heparin
after hemorrhageafter hemorrhage
 Most common drug-inducedMost common drug-induced
thrombocytopeniathrombocytopenia
 A large number of patients receive heparinA large number of patients receive heparin
in the hospital environment.in the hospital environment.

28. Non-immune heparin-associatedNon-immune heparin-associated
thrombocytopenia (“HIT Type I”)thrombocytopenia (“HIT Type I”)
 BenignBenign
 Up to 10% patients on heparinUp to 10% patients on heparin
 Rapid decline in platelet count within first 2Rapid decline in platelet count within first 2
days of heparin administrationdays of heparin administration
 Platelet count >100 000/ulPlatelet count >100 000/ul
 Returns to normal within 5 days despiteReturns to normal within 5 days despite
continued heparin use (or within 2 days ifcontinued heparin use (or within 2 days if
heparin is stopped).heparin is stopped).

29. Heparin-inducedHeparin-induced
thrombocytopenia: “HIT type 2”thrombocytopenia: “HIT type 2”
 Potentially catastrophic thrombosis (Heparin-Potentially catastrophic thrombosis (Heparin-
induced thrombocytopenia and thrombosis)induced thrombocytopenia and thrombosis)
 8% of patients on heparin develop antibody8% of patients on heparin develop antibody
without becoming thrombocytopenicwithout becoming thrombocytopenic
 1-5% patients on heparin develop1-5% patients on heparin develop
thrombocytopaeniathrombocytopaenia
 Of those with thrombocytopaenia, 30% developOf those with thrombocytopaenia, 30% develop
venous and/or arterial thrombosisvenous and/or arterial thrombosis
 Bleeding uncommonBleeding uncommon

30. Treatment of HITTreatment of HIT
 Discontinue all heparinDiscontinue all heparin
 If need to continue anti-coagulation, useIf need to continue anti-coagulation, use
danaparoid (orgaran).danaparoid (orgaran).
 AvoidAvoid platelet transfusionsplatelet transfusions
 Thrombosis: use danaparoid or thrombinThrombosis: use danaparoid or thrombin
inhibitorinhibitor

31. Heparin induced bleedingHeparin induced bleeding
– in 1-33% of patientsin 1-33% of patients
– sometimes majorsometimes major
– is the major adverse effectis the major adverse effect
– to prevent:to prevent:
» adequate patient selectionadequate patient selection
» careful control of dosagecareful control of dosage
» close monitoring of the aPTTclose monitoring of the aPTT

32. Heparin: AntagonistsHeparin: Antagonists
 Heparin’s effect can be reversed by the useHeparin’s effect can be reversed by the use
ofof protamine sulfateprotamine sulfate (inactivates heparin(inactivates heparin
by binding tightly to it)by binding tightly to it)
 Minor bleeding does not usually require anMinor bleeding does not usually require an
antagonistantagonist
– Effects of heparin disappears a few hours afterEffects of heparin disappears a few hours after
last injectionlast injection

33. LOW MOLECULAR WEIGHTLOW MOLECULAR WEIGHT
HEPARINHEPARIN

34. Low Molecular Weight HeparinsLow Molecular Weight Heparins
 Low molecular weight forms of heparin doLow molecular weight forms of heparin do
not catalyze the inhibition of thrombin bynot catalyze the inhibition of thrombin by
antithrombinantithrombin
» Their main effect is through a catalytic effect onTheir main effect is through a catalytic effect on
the inhibition of factor Xa by antithrombinthe inhibition of factor Xa by antithrombin
 Example of available preparations:Example of available preparations:
Enoxaparin (Clexane)Enoxaparin (Clexane)
Dalteparin (Fragmin)Dalteparin (Fragmin)
Tinzaparin (Inohep)Tinzaparin (Inohep)
Nadroparin (Fraxiparine)Nadroparin (Fraxiparine)

35. Low Molecular Weight Heparins (II)Low Molecular Weight Heparins (II)
 As effective as standard heparin in mostAs effective as standard heparin in most
applicationsapplications
 Given subcutaneously in fixed or weightGiven subcutaneously in fixed or weight
adjusted dosage (once or twice daily)adjusted dosage (once or twice daily)
 Monitoring not required because of moreMonitoring not required because of more
predictable pharmacokinetic profilepredictable pharmacokinetic profile

36. Differences in Mechanism of ActionDifferences in Mechanism of Action
 Any size of heparin chain can inhibit the action ofAny size of heparin chain can inhibit the action of
factor Xa by binding to antithrombin (AT)factor Xa by binding to antithrombin (AT)
 In contrast, in order to inactivate thrombin (IIa),In contrast, in order to inactivate thrombin (IIa),
the heparin molecule must be long enough to bindthe heparin molecule must be long enough to bind
both antithrombin and thrombinboth antithrombin and thrombin
 Less than half of the chains of LMWH are longLess than half of the chains of LMWH are long
enoughenough

37. Advantages of LMWH over UFHAdvantages of LMWH over UFH
 No need for laboratory monitoringNo need for laboratory monitoring
 Higher bioavailability: 90% vs 30%Higher bioavailability: 90% vs 30%
 Longer plasma half lifeLonger plasma half life
- 4-6 hours vs 0.5 -1 hour- 4-6 hours vs 0.5 -1 hour
- renal (slower) vs hepatic clearancerenal (slower) vs hepatic clearance
 Less inhibition of platelet functionLess inhibition of platelet function
 Lower incidence of HITLower incidence of HIT

38. LMWH: IndicationsLMWH: Indications
Venous Thromboembolism (VTE)Venous Thromboembolism (VTE)
Treatment/ProphylaxisTreatment/Prophylaxis
Acute Coronary Syndrome (ACS)Acute Coronary Syndrome (ACS)
New onset of Atrial Fibrillation (AF)New onset of Atrial Fibrillation (AF)
(in clinical practice, same indications as(in clinical practice, same indications as
UFH)UFH)

39. LMWH: ContraindicationsLMWH: Contraindications
Active bleedingActive bleeding
Hypersensitivity to heparin/porkHypersensitivity to heparin/pork
ThrombocytopeniaThrombocytopenia
History of heparin –inducedHistory of heparin –induced
thrombocytopenia (HIT) or heparin-thrombocytopenia (HIT) or heparin-
induced thrombocytopenia/thrombosisinduced thrombocytopenia/thrombosis
(HITT)(HITT)

40. LMWH: Side effectsLMWH: Side effects
BleedingBleeding
Injection site hematoma and/or ecchymosisInjection site hematoma and/or ecchymosis
Tissue necrosisTissue necrosis
ThrombocytopeniaThrombocytopenia

41. LMWH: Drug & Food InteractionsLMWH: Drug & Food Interactions
– Herbs/ NutraceuticalsHerbs/ Nutraceuticals:: eveningevening
primrose,, garlic, ginger, ginkgo, greenprimrose,, garlic, ginger, ginkgo, green
tea, ginsengtea, ginseng
– Drugs:Drugs: warfarin, aspirin, NSAIDs,warfarin, aspirin, NSAIDs,
dipyridamole, ticlopidine, clopidogreldipyridamole, ticlopidine, clopidogrel
and GP IIb/IIIa antagonistsand GP IIb/IIIa antagonists

42. Monitoring of LMWHMonitoring of LMWH
CBC - Platelets, Hemoglobin, HCTCBC - Platelets, Hemoglobin, HCT
Cr – Serum CreatinineCr – Serum Creatinine
Anti-factor Xa level in severe obesityAnti-factor Xa level in severe obesity
(>150 kg) and/or CrCl <30ml/hr: recheck(>150 kg) and/or CrCl <30ml/hr: recheck
3-5 hours after administration.*3-5 hours after administration.*
Recommended reference rangeRecommended reference range
(enoxaparin) 0.6-1 International units/ml(enoxaparin) 0.6-1 International units/ml

43. LMWH vs. UnfractionatedLMWH vs. Unfractionated
HEPARINHEPARIN
LMWH vs. UnfractionatedLMWH vs. Unfractionated
HEPARINHEPARIN
withwith
• ImprovedImproved
pharmacokineticspharmacokinetics
especially subcutaneousespecially subcutaneous
routeroute
• Little effect in APTT soLittle effect in APTT so
monitoring not usuallymonitoring not usually
requiredrequired **
• less likely to causeless likely to cause
thrombo- cytopenia orthrombo- cytopenia or
osteoporosis long-termosteoporosis long-term
againstagainst
• Cannot beCannot be
monitored by APTTmonitored by APTT
-- specific anti-Xaspecific anti-Xa
assay neededassay needed
• Not fully reversedNot fully reversed
by protamineby protamine
• Expensive (10-20-Expensive (10-20-
fold more than UFH)fold more than UFH)

44. Synthetic selective inhibitors of factor XaSynthetic selective inhibitors of factor Xa
 New class of synthetic selective inhibitorsNew class of synthetic selective inhibitors
of factor Xaof factor Xa are the novelty as heparinare the novelty as heparin
replacementsreplacements
 FondaparinuxFondaparinux andand idraparinuxidraparinux
 Fondaparinux given s.c. once a dayFondaparinux given s.c. once a day
 No monitoring necessaryNo monitoring necessary
 Better than LMWH?Better than LMWH?

45. WARFARINWARFARIN

46. Vitamin KVitamin K
Synthesis ofSynthesis of
FunctionalFunctional
CoagulationCoagulation
FactorsFactors
VIIVII
IXIX
XX
IIII
Vitamin K-Dependent ClottingVitamin K-Dependent Clotting
FactorsFactors

47. Vitamin K Mechanism of ActionVitamin K Mechanism of Action

48. Warfarin Mechanism of ActionWarfarin Mechanism of Action
Inactive factors II,Inactive factors II,
VII, IX, and XVII, IX, and X
Proteins S and CProteins S and C
Active factors II,Active factors II,
VII, IX, and XVII, IX, and X
Proteins S and CProteins S and C
Vitamin K epoxideVitamin K epoxide
Vitamin K reducedVitamin K reduced
WARFARINWARFARIN
Prevents the reduction of vitamin K, which is essential for activationPrevents the reduction of vitamin K, which is essential for activation
of certain factorsof certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
The delayed onset of Warfarin effect actually reflects the half-lives of
these modified clotting factors (shortest, Factor VII 6h; longest, Factor
II 40-60h).

49. Warfarin: IndicationsWarfarin: Indications
– Atrial fibrillation or flutterAtrial fibrillation or flutter
– Post myocardial infarctionPost myocardial infarction
– Mechanical heart valveMechanical heart valve
– Coronary heart diseaseCoronary heart disease
– Elective cardioversionElective cardioversion
– Mechanical prosthetic valveMechanical prosthetic valve
– VTE treatment/prophylaxisVTE treatment/prophylaxis
– Joint replacementJoint replacement
– Hypercoagulable statesHypercoagulable states

50. Warfarin: ContraindicationsWarfarin: Contraindications
– HypersensitivityHypersensitivity
– Hemorrhagic tendenciesHemorrhagic tendencies
– Recent/potential surgery of the eye or CNSRecent/potential surgery of the eye or CNS
– Major regional lumbar block anesthesia or surgeryMajor regional lumbar block anesthesia or surgery
– blood dyscrasiasblood dyscrasias
– Severe uncontrolled hypertensionSevere uncontrolled hypertension
– Pericarditis/pericardial effusionPericarditis/pericardial effusion
– Subacute bacterial endocarditisSubacute bacterial endocarditis
– History of warfarin-induced necrosisHistory of warfarin-induced necrosis
– Significant fall riskSignificant fall risk
– Eclampsia/pre-eclampsia , threatened abortion,Eclampsia/pre-eclampsia , threatened abortion,

51. Relative Contraindications to WarfarinRelative Contraindications to Warfarin
TherapyTherapy
 PregnancyPregnancy
 Situations where the risk of hemorrhage isSituations where the risk of hemorrhage is
greater than the potential clinical benefits ofgreater than the potential clinical benefits of
therapytherapy
– Uncontrolled alcohol/drug abuseUncontrolled alcohol/drug abuse
– Unsupervised dementia/psychosisUnsupervised dementia/psychosis

52. Warfarin:Warfarin: DosingDosing
– Based on indication, goal INR, andBased on indication, goal INR, and
patient response (INR/PT). Usual initialpatient response (INR/PT). Usual initial
dose isdose is 5mg/day5mg/day, 2.5mg/day in elderly,, 2.5mg/day in elderly,
severe liver disease.severe liver disease.
» Must have baseline INR prior to initiationMust have baseline INR prior to initiation
» Must have current INR for monitoring andMust have current INR for monitoring and
dosage adjustmentdosage adjustment
– CoadministrationCoadministration
» HeparinHeparin
» ClopidogrelClopidogrel
» LMWHLMWH
» AspirinAspirin

53. Warfarin: AdministrationWarfarin: Administration
– Same time each daySame time each day
– Verify dose prior to administrationVerify dose prior to administration
»Ensure current INR availableEnsure current INR available
– TabletsTablets
»OrallyOrally
»Dispensed in unit-dose (inpatient use)Dispensed in unit-dose (inpatient use)

54. Warfarin: Side effectsWarfarin: Side effects
BleedingBleeding
Skin necrosisSkin necrosis
““Purple toes” syndromePurple toes” syndrome

55. Warfarin: MonitoringWarfarin: Monitoring
 Labs for Monitoring Include:Labs for Monitoring Include:
– INRINR
– PTPT
– CBCCBC
– LFTsLFTs
– Stool guaiac testStool guaiac test
– Anti-Factor Xa (if available)Anti-Factor Xa (if available)
– b HCG (when appropriate)b HCG (when appropriate)

56. Warfarin: Food InteractionsWarfarin: Food Interactions
– Vitamin K containing foods, dietaryVitamin K containing foods, dietary
supplements, OTCs may cause change insupplements, OTCs may cause change in
warfarin’s therapeutic effectwarfarin’s therapeutic effect
– Key is to maintain dietary consistency andKey is to maintain dietary consistency and
notify provider of any changesnotify provider of any changes

57. Some relevant interactions with oral anticoagulants
Increased PT Decreased PT
Pharmacokinetic Pharmacodynamic Pharmacokinetic Pharmacodynamic
Amiodarone
Cimetidine
Metronidazole
Fluconazole
Phenylbutazone
Trimethoprim-
sulfamethoxazole
Drugs:
Aspirin
Cephalosporins
(3rd
generation)
Heparin
Diseases:
Hepatic disease
Hyperthyroidism
Barbiturates
Cholestyramine
Rifampin
Drugs:
Diuretics
Vitamin K
Diseases:
Resistance
(hereditary)
Hypothyroidism
Modified from Katzung, 9th
edition

58. Special Considerations in the ElderlySpecial Considerations in the Elderly
—Bleeding—Bleeding
 Increased age associated with increasedIncreased age associated with increased
sensitivity at usual dosessensitivity at usual doses
 ComorbidityComorbidity
 Increased drug interactionsIncreased drug interactions
 ? Increased bleeding risk independent of the? Increased bleeding risk independent of the
aboveabove

59. Prothrombin Time (PT)Prothrombin Time (PT)
 Historically, a most reliable and “relied upon”Historically, a most reliable and “relied upon”
clinical testclinical test
However:However:
– Proliferation of thromboplastin reagents with widelyProliferation of thromboplastin reagents with widely
varying sensitivities to reduced levels of vitamin K-varying sensitivities to reduced levels of vitamin K-
dependent clotting factors has occurreddependent clotting factors has occurred
– Concept of correct “intensity” of anticoagulant therapyConcept of correct “intensity” of anticoagulant therapy
has changed significantly (low intensity)has changed significantly (low intensity)
– Problem addressed by use of INR (InternationalProblem addressed by use of INR (International
Normalized Ratio)Normalized Ratio)

60. J Clin Path 1985; 38:133-134; WHO Tech Rep Ser. #687 983J Clin Path 1985; 38:133-134; WHO Tech Rep Ser. #687 983..
INR: International NormalizedINR: International Normalized
RatioRatio
 A mathematical “correction” (of the PT ratio) forA mathematical “correction” (of the PT ratio) for
differences in the sensitivity of thromboplastindifferences in the sensitivity of thromboplastin
reagentsreagents
 Relies upon “reference” thromboplastins withRelies upon “reference” thromboplastins with
known sensitivity to antithrombotic effects of oralknown sensitivity to antithrombotic effects of oral
anticoagulantsanticoagulants
 INR is the PT ratio one would have obtained if theINR is the PT ratio one would have obtained if the
“reference” thromboplastin had been used“reference” thromboplastin had been used
 Allows for comparison of results between labs andAllows for comparison of results between labs and
standardizes reporting of the prothrombin timestandardizes reporting of the prothrombin time

61. )) ((Patient’s PT in SecondsPatient’s PT in Seconds
Mean Normal PT in SecondsMean Normal PT in Seconds
INRINR==
ISIISI
INR = International Normalized RatioINR = International Normalized Ratio
ISI = International Sensitivity IndexISI = International Sensitivity Index
INR EquationINR Equation

62. Potential Problems with the INRPotential Problems with the INR
LimitationsLimitations
 Unreliable during inductionUnreliable during induction
 Loss of accuracy with high ISILoss of accuracy with high ISI
thromboplastinsthromboplastins
 Incorrect ISI assignment byIncorrect ISI assignment by
manufacturermanufacturer
 Incorrect calculation of INR dueIncorrect calculation of INR due
to failure to use proper meanto failure to use proper mean
normal plasma value to derivenormal plasma value to derive
PT ratioPT ratio
SolutionsSolutions
 Use thromboplastin reagentsUse thromboplastin reagents
with low ISI values (less thanwith low ISI values (less than
1.5)1.5)
 Use thromboplastin reagentsUse thromboplastin reagents
with low ISI valueswith low ISI values
 Use thromboplastin reagentsUse thromboplastin reagents
with low ISI values and usewith low ISI values and use
plasma calibrants with certifiedplasma calibrants with certified
INR valuesINR values
 Use “mean normal” PT derivedUse “mean normal” PT derived
from normal plasma samples forfrom normal plasma samples for
every new batch ofevery new batch of
thromboplastin reagentthromboplastin reagent

63. Dose Correction of warfarinDose Correction of warfarin
 INR < 2INR < 2:: increaseincrease weeklyweekly warfarinwarfarin dose bydose by 5 – 20 %5 – 20 %
 3 < INR < 5:3 < INR < 5: decrease weeklydecrease weekly warfarinwarfarin dose bydose by 5 – 20 %5 – 20 %
 5 < INR < 95 < INR < 9 w/o bleedingw/o bleeding:: nono warfarinwarfarin forfor 1-21-2 daysdays,,
and/orand/or 1 – 2,5 mg vitamin1 – 2,5 mg vitamin KK (Konakion 2, 10 mg),(Konakion 2, 10 mg), andand reduce thereduce the
weekly dose ofweekly dose of warfarinwarfarin
 5 < INR < 95 < INR < 9 w bleedingw bleeding oror INR > 9:INR > 9: nono warfarin, 5 – 10 mg vitaminwarfarin, 5 – 10 mg vitamin
KK,, reduce weekly dose ofreduce weekly dose of warfarinwarfarin
 MassMassiivvee bleedingbleeding:: aPCCaPCC oror FFPFFP oror rereccombinombinantant factorfactor VIIaVIIa
(Novoseven, 90(Novoseven, 90 µµg/g/bwbwkgkg everyevery 22 hourshours)) andand 10 mg10 mg vvitaminitamin KK
(7th
ACCP Conference. Chest 2004;126;204 – 233)

64. Conversion from Heparin toConversion from Heparin to
WarfarinWarfarin
 May begin concomitantly with heparinMay begin concomitantly with heparin
therapytherapy
 Heparin should be continued for a minimumHeparin should be continued for a minimum
of four daysof four days
– Time to peak antithrombotic effect of warfarinTime to peak antithrombotic effect of warfarin
is delayed 96 hours (despite INR)is delayed 96 hours (despite INR)
 When INR reaches desired therapeuticWhen INR reaches desired therapeutic
range, discontinue heparin (after arange, discontinue heparin (after a
minimum of four days)minimum of four days)

65. Signs of Warfarin OverdosageSigns of Warfarin Overdosage
 Any unusual bleeding:Any unusual bleeding:
– Blood in stools or urineBlood in stools or urine
– Excessive menstrual bleedingExcessive menstrual bleeding
– BruisingBruising
– Excessive nose bleeds/bleeding gumsExcessive nose bleeds/bleeding gums
– Persistent oozing from superficial injuriesPersistent oozing from superficial injuries
– Bleeding from tumor, ulcer, or other lesionBleeding from tumor, ulcer, or other lesion

66. Indication INR Range TargetIndication INR Range Target
Prophylaxis of venous thrombosis (high-risk surgery) 2.0–3.0Prophylaxis of venous thrombosis (high-risk surgery) 2.0–3.0 2.52.5
Treatment of venous thrombosisTreatment of venous thrombosis
Treatment of PETreatment of PE
Prevention of systemic embolismPrevention of systemic embolism
Tissue heart valvesTissue heart valves
AMI (to prevent systemic embolism)AMI (to prevent systemic embolism)
Valvular heart diseaseValvular heart disease
Atrial fibrillationAtrial fibrillation
Mechanical prosthetic valves (high risk) 2.5–3.5 3.0Mechanical prosthetic valves (high risk) 2.5–3.5 3.0
Certain patients with thrombosis and the antiphospholipid syndromeCertain patients with thrombosis and the antiphospholipid syndrome
AMI (to prevent recurrent AMI)AMI (to prevent recurrent AMI)
Bileaflet mechanical valve in aortic position, NSR 2.0–3.0Bileaflet mechanical valve in aortic position, NSR 2.0–3.0 2.52.5
Warfarin: Current Indications/IntensityWarfarin: Current Indications/Intensity

67. FIBRINOLYTIC THERAPYFIBRINOLYTIC THERAPY

68. FibrinolysisFibrinolysis

69. Fibrinolytic DrugsFibrinolytic Drugs
 Catalyse the formation ofCatalyse the formation of plasminplasmin fromfrom
plasminogen, leading to theplasminogen, leading to the lysis of thrombilysis of thrombi
 InduceInduce generalized lysisgeneralized lysis of thrombi if givenof thrombi if given
intravenously,intravenously, both of the protectiveboth of the protective
haemostatic thrombi and the targetedhaemostatic thrombi and the targeted
pathological thrombipathological thrombi
 Their main use isTheir main use is after myocardial infarctionafter myocardial infarction

70. StreptokinaseStreptokinase
 Not an enzymeNot an enzyme
 Protein synthesized by β-hemolyticProtein synthesized by β-hemolytic
streptococcistreptococci
 Combines withCombines with proactivator ofproactivator of
plasminogenplasminogen, forming complex that catalyses, forming complex that catalyses
conversion of plasminogen to plasminconversion of plasminogen to plasmin
 Risk of serious allergic reactionRisk of serious allergic reaction when givenwhen given
a second timea second time

71. Tissue Plasminogen Activators (tPA)Tissue Plasminogen Activators (tPA)
 Product of recombinant DNA technologyProduct of recombinant DNA technology
 Preferentially activate plasminogen that isPreferentially activate plasminogen that is
bound to fibrinbound to fibrin
 In theory, limit fibrinolysis to formedIn theory, limit fibrinolysis to formed
thrombi, avoiding systemic activationthrombi, avoiding systemic activation

72. Fibrinolytic Drugs: Clinical UsesFibrinolytic Drugs: Clinical Uses
 acute myocardial infarctionacute myocardial infarction
 multiple pulmonary embolismmultiple pulmonary embolism
 central deep vein thrombosiscentral deep vein thrombosis
 Ischemic stroke within 90 minutes of onsetIschemic stroke within 90 minutes of onset
 Intravenous administrationIntravenous administration
 Most physicians will not administer streptokinaseMost physicians will not administer streptokinase
a second time because of risk of allergica second time because of risk of allergic
phenomenaphenomena

73. Anti-Platelet DrugsAnti-Platelet Drugs

74. Anti-Platelet DrugsAnti-Platelet Drugs
 Platelets form first hemostatic plugPlatelets form first hemostatic plug
– In theory, depressing platelet function might beIn theory, depressing platelet function might be
negativenegative
 But:But:
– Platelets also participate in reactions leading toPlatelets also participate in reactions leading to
atherosclerosis and thrombosisatherosclerosis and thrombosis
 Therefore, antagonists of platelet functionTherefore, antagonists of platelet function
are used inare used in prophylaxis of thrombosisprophylaxis of thrombosis andand
to alter the evolution of atherosclerosisto alter the evolution of atherosclerosis

75. AspirinAspirin
 By far, most widely used anti-platelet drugBy far, most widely used anti-platelet drug
 Blocks the production ofBlocks the production of thromboxane Athromboxane A22 byby
covalentlycovalently acetylatingacetylating the serine residue nearthe serine residue near
the active site ofthe active site of cyclooxygenasecyclooxygenase
 Action is irreversibleAction is irreversible
– new platelets have to be produced for the effectnew platelets have to be produced for the effect
to disappear (7-10 days)to disappear (7-10 days)
 A small daily dose is enough for maximalA small daily dose is enough for maximal
effecteffect

76. ClopidogrelClopidogrel
 For patients intolerant to aspirinFor patients intolerant to aspirin
 No effect on prostaglandin metabolismNo effect on prostaglandin metabolism
 ReducesReduces platelet aggregation byplatelet aggregation by inhibiting theinhibiting the
ADP pathway in plateletsADP pathway in platelets, inducing a, inducing a
thrombasthenia-like statethrombasthenia-like state
 Seemed safe, but recently cases of induction ofSeemed safe, but recently cases of induction of
thrombotic thrombocytopenic purpura (TTP)thrombotic thrombocytopenic purpura (TTP) havehave
been reportedbeen reported
– However, risk may be lower than with ticlodipineHowever, risk may be lower than with ticlodipine

77. AbciximabAbciximab
 Mouse/human chimeric monoclonalMouse/human chimeric monoclonal
antibodyantibody
 Blocks platelet glycoprotein receptorsBlocks platelet glycoprotein receptors
 Used in association with aspirin and heparinUsed in association with aspirin and heparin
in patients undergoing high-risk angioplastyin patients undergoing high-risk angioplasty

78. 33rdrd
part:part:
Clinical PharmacologyClinical Pharmacology
 Use of some of the drugs discussed today involvesUse of some of the drugs discussed today involves
a substantial risk of serious bleeding, even deatha substantial risk of serious bleeding, even death
 Very important to assess risk/benefit ratioVery important to assess risk/benefit ratio
 Prophylaxis:Prophylaxis:
– because of low frequency of the end-point eventsbecause of low frequency of the end-point events
(myocardial infarction, stroke, death), studies have to(myocardial infarction, stroke, death), studies have to
use large numbers of patients to achieve statisticaluse large numbers of patients to achieve statistical
significant resultssignificant results
 We will now review clinical use of drugsWe will now review clinical use of drugs
discussed todaydiscussed today

79. Venous Thromboembolism +Venous Thromboembolism +
pulmonary embolismpulmonary embolism::
 Objective: to prevent recurrent,Objective: to prevent recurrent,
sometimes fatal, pulmonarysometimes fatal, pulmonary
embolismembolism
 Deep vein thrombosis above theDeep vein thrombosis above the
knee joint complicated byknee joint complicated by
pulmonary embolism:pulmonary embolism:
– Traditional wayTraditional way
» Maximum doses of heparin given byMaximum doses of heparin given by
vascular infusion for 7-10 daysvascular infusion for 7-10 days
» Then heparin replaced by warfarinThen heparin replaced by warfarin
(necessary to(necessary to overlap both drugs foroverlap both drugs for
3-5 days3-5 days).). Treatment for 3-6Treatment for 3-6
monthsmonths
» Often, both drugs started at same timeOften, both drugs started at same time
» If warfarin cannot be given (e.g.,If warfarin cannot be given (e.g.,
pregnancy), subcutaneous high or lowpregnancy), subcutaneous high or low
molecular weight heparin is usedmolecular weight heparin is used

80. Venous Thromboembolism +Venous Thromboembolism +
pulmonary embolism (II)pulmonary embolism (II)
 Modern approach:Modern approach:
– Low molecular weight heparin!Low molecular weight heparin!
» Studies show that it is as effective as high molecularStudies show that it is as effective as high molecular
weight heparinweight heparin
– Followed by warfarinFollowed by warfarin

81. Is There a Role for FibrinolyticIs There a Role for Fibrinolytic
Agents in Pulmonary EmbolismAgents in Pulmonary Embolism??
 Yes, if multiple emboli. Some studies showYes, if multiple emboli. Some studies show
reduced mortalityreduced mortality
 Yes, if massive embolism and emergencyYes, if massive embolism and emergency
surgical removal cannot be donesurgical removal cannot be done

82. Venous Thromboembolism (Venous Thromboembolism (nono
pulmonary embolismpulmonary embolism))
 If deep vein thrombosis isIf deep vein thrombosis is
above knee jointabove knee joint but nobut no
pulmonary embolism:pulmonary embolism:
– Same approach as in the case ofSame approach as in the case of
pulmonary embolismpulmonary embolism
 IfIf below knee jointbelow knee joint (calf):(calf):
– Anticoagulant therapy often notAnticoagulant therapy often not
usedused
– Repeated venous DopplerRepeated venous Doppler
studies to monitor endogenousstudies to monitor endogenous
fibrinolysisfibrinolysis

83. Venous Thromboembolism:Venous Thromboembolism:
PreventionPrevention
 Early ambulation post surgeryEarly ambulation post surgery
 In moderate risk patients (e.g., general surgeryIn moderate risk patients (e.g., general surgery
>30 min in patients >40 years of age),>30 min in patients >40 years of age), low doselow dose
subcutaneous heparinsubcutaneous heparin oror low molecular weightlow molecular weight
heparinheparin have been recommendedhave been recommended
– No increased surgical bleeding but risk of increasedNo increased surgical bleeding but risk of increased
haematoma of surgical woundhaematoma of surgical wound
– Alternative to heparin: compression of legsAlternative to heparin: compression of legs

84. Venous Thromboembolism:Venous Thromboembolism:
Prevention (2)Prevention (2)
 Surgery in higher risk patients:Surgery in higher risk patients:
– Pneumatic compression of legs + low-dosePneumatic compression of legs + low-dose
heparin s.c. or low molecular weight heparinheparin s.c. or low molecular weight heparin
 Hip replacement surgery:Hip replacement surgery:
– Low molecular weight heparin now first choiceLow molecular weight heparin now first choice

85. Myocardial InfarctionMyocardial Infarction
 ConsiderConsider fibrinolytic therapyfibrinolytic therapy in all casesin all cases
– Shown to reduce mortality and cardiac muscle lossShown to reduce mortality and cardiac muscle loss
 Either streptokinase or tPAEither streptokinase or tPA
 First 6 hours after infarctionFirst 6 hours after infarction
 Aspirin to prevent re-occlusionAspirin to prevent re-occlusion
– Usually, patients kept on low dose aspirinUsually, patients kept on low dose aspirin
 Long-termLong-term oral anticoagulantoral anticoagulant therapy indicatedtherapy indicated
onlyonly if there is atrial fibrillation or other risk factorsif there is atrial fibrillation or other risk factors
 Beta-blockers given after infarction reduceBeta-blockers given after infarction reduce
mortality (secondary prevention).mortality (secondary prevention).

86. Unstable AnginaUnstable Angina
 Pre-myocardial infarction conditionPre-myocardial infarction condition
 Patient should be put in hospital and treatedPatient should be put in hospital and treated
with intravenous heparin (alternative: lowwith intravenous heparin (alternative: low
molecular weight heparin) + aspirinmolecular weight heparin) + aspirin
followed by warfarinfollowed by warfarin

87. Atrial FibrillationAtrial Fibrillation
 Risk of strokeRisk of stroke
 Frequently undiagnosedFrequently undiagnosed
 Most patients medicated with warfarinMost patients medicated with warfarin
– Aspirin acceptable in some lower risk patientsAspirin acceptable in some lower risk patients
or if warfarin cannot be given (e.g., pregnancy)or if warfarin cannot be given (e.g., pregnancy)
 Warfarin clearly recommended prior toWarfarin clearly recommended prior to
elective cardioversionelective cardioversion
– Start 3 weeks prior to procedure and keep for 1Start 3 weeks prior to procedure and keep for 1
month if sinus rhythm has been restoredmonth if sinus rhythm has been restored

88. Patients with valvular heartPatients with valvular heart
disease or prosthetic valvesdisease or prosthetic valves
 Mitral disease + atrial fibrillationMitral disease + atrial fibrillation →→
warfarin indicated because of high risk ofwarfarin indicated because of high risk of
strokestroke
– Many cardiologists will prescribe warfarin ifMany cardiologists will prescribe warfarin if
left atrium is substantially enlarged in absenceleft atrium is substantially enlarged in absence
of fibrillation (fibrillation not diagnosed rightof fibrillation (fibrillation not diagnosed right
away)away)
 If warfarin cannot be given, aspirin isIf warfarin cannot be given, aspirin is
indicatedindicated

89. Cerebrovascular DiseaseCerebrovascular Disease
 Aspirin is indicated for prophylaxis followingAspirin is indicated for prophylaxis following
transient ischemic attacks or complete ischemictransient ischemic attacks or complete ischemic
strokes (given for life)strokes (given for life)
 In ischemic strokes caused by embolism (~15%),In ischemic strokes caused by embolism (~15%),
heparin followed by warfarin may be indicatedheparin followed by warfarin may be indicated
– Controversial: risk of converting ischemic intoControversial: risk of converting ischemic into
hemorrhagic strokehemorrhagic stroke
– Such approach can be considered if no hypertension andSuch approach can be considered if no hypertension and
CT scan shows no bleedingCT scan shows no bleeding
 Fibrinolytic therapyFibrinolytic therapy →→ controversial (high risk) butcontroversial (high risk) but
some brilliant successes (issue to be discussed insome brilliant successes (issue to be discussed in
small group)small group)

90. Peripheral Arterial OcclusionPeripheral Arterial Occlusion
 If a major artery is occluded,If a major artery is occluded, fibrinolyticfibrinolytic
therapy can be consideredtherapy can be considered onlyonly if surgeryif surgery
not possible or has to be delayednot possible or has to be delayed
 Fibrinolytic therapy may rescue a limb, butFibrinolytic therapy may rescue a limb, but
involves risksinvolves risks

91. Arterial Thromboembolism:Arterial Thromboembolism:
Primary PreventionPrimary Prevention
 Aspirin has clear benefit in preventing strokes andAspirin has clear benefit in preventing strokes and
myocardial infarction in aging populationmyocardial infarction in aging population
 But studies show increase in hemorrhagic strokesBut studies show increase in hemorrhagic strokes
in normal aging individuals taking one aspirin perin normal aging individuals taking one aspirin per
dayday
 Therefore, indicated ONLY if other risk factorsTherefore, indicated ONLY if other risk factors
are presentare present
 Do not forget that a low dose of aspirin is all thatDo not forget that a low dose of aspirin is all that
is needed!is needed!

92. Thank YouThank You