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
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,
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)
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
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?
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).
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
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
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
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
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!
“ Anticoagulation is a high-risk treatment, which commonly leads to adverse drug events due to the complexity of dosing these medications, monitoring their effects, and ensuring patient compliance with outpatient therapy.”*
Until approximately 1980, the only two types of anticoagulants in clinical use were heparin and the vitamin K antagonists. LMWH followed and in many countries has replaced unfractionated heparin (UHF) for the treatment of venous thrombosis. 3 More recently, two other new anticoagulants have been introduced: danaproid* and hirudin*. Danaparoid, a heparinoid that has much less cross-reactivity than LMWH in patients with heparin-induced thrombocytopenia (HIT) has been used successfully to treat patients with thrombosis and HIT. 27 Hirudin (recombinant; lepirudin) does not cross react with HIT antibodies and is now the drug of choice for the treatment of venous thromboembolism in patients with HIT. 28,29 Two other new anticoagulants are in clinical trials for the prevention and treatment of venous thrombosis: a synthetic pentasaccharide* with high affinity for antithrombin and an oral small-molecule direct thrombin inhibitor.* *Danaparoid is not approved by the FDA for use in the treatment of thrombosis or HIT. 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. 3. Hirsh. Chest. 1998;114:489S-510S 27. Chong BH. Heparin-Induced Thrombocytopenia . 2000;291-311. 28. Greinacher. Circulation 1999;100:587-593. 29. Greinacher. Blood 2000, in press. The highlights of current anticoagulant therapy are shown on this slide. During the past two decades, an empirical approach to clinical decision-making has largely been replaced by an evidence-based approach to treating thromboembolic disease. 2,3 Firm evidence now exists in support of the following treatment strategies: an initial course of heparin is necessary 4 ; the induction period with heparin or low-molecular-weight heparin (LMWH) can be reduced to 5 days for most patients 5,6 ; continued with treatment for months after hospital discharge is required 7-10 ; LMWH can be used instead of heparin 11,12 ; and the optimal therapeutic range is an International Normalized Ratio (INR) of 2.0 to 3.0 for most patients. 3,13 The optimal duration of anticoagulation has yet to be established for patients with VTE: in particular, those with idiopathic venous thrombosis and patients with thrombophilia. 1,14 Finally, after 50 years of having a single class of oral anticoagulants available for clinical use, a new oral small-molecule direct thrombin inhibitor* is being evaluated as an alternative to warfarin. Orgaran (danaparoid sodium) The antithrombotic agent danaparoid sodium (Orgaran,) is a mixture of the following glycosaminoglycans: Heparan sulphate 83% Dermatan sulphate 12% Chondroitin sulphate 5% Orgaran exerts its major anticoagulant effect by catalysing inactivation of factor Xa by Antithrombin. It also has some anti-Thrombin (IIa) effect but the ratio of anti-Xa to anti-IIa effect is greater than 28:1. Orgaran is a non-heparin of proven efficacy in thrombotic disorders and is approved and available for use in the UK for the treatment of HIT complicated by thromboembolism.
This slide identifies the sites of action of warfarin, heparin, and LMWH. The production of factors VII, IX,X and II (yellow) is suppressed by warfarin (WARF). Factors IIa (thrombin), Xa, and IXa (BLUE) are inactivated by heparin (UFH) and LMWH in an antithrombin-dependent manner. LMWH has relatively greater anti-Xa activity than anti-IIa (antithrombin) activity . This slide identifies the sites of action of the new anticoagulants. Pentasaccharide (PENTASAC)* & (FONDAPARINAUX) inactivates factor Xa in an antithrombin-dependent manner.The direct thrombin inhibitors hirudin and the oral thrombin inhibitor (ORAL SMALL-MOLECULE DTI) inhibit factor IIa (thrombin) independently of antithrombin. The antithrombotic agent danaparoid sodium (Orgaran) is a mixture of the following glycosaminoglycans: Heparan sulphate 83% Dermatan sulphate 12% Chondroitin sulphate 5% Orgaran exerts its major anticoagulant effect by catalysing inactivation of factor Xa by Antithrombin. It also has some anti-Thrombin (IIa) effect but the ratio of anti-Xa to anti-IIa effect is greater than 28:1. Orgaran is a non-heparin of proven efficacy in thrombotic disorders and is approved and available for use in the UK for the treatment of HIT complicated by thromboembolism.
Heparin (from Ancient Greek ηπαρ ( hepar ), liver), also known as unfractionated heparin , a highly sulfated glycosaminoglycan, Native heparin is a polymer with a molecular weight ranging from 3 kDa to 30 kDa, although the average molecular weight of most commercial heparin preparations is in the range of 12 kDa to 15 kDa. Heparin is a member of the glycosaminoglycan family of carbohydrates (which includes the closely related molecule heparan sulphate) and consists of a variably sulfated repeating disaccharide unit. Heparin is a naturally occurring anticoagulant produced by basophils and mast cells.Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to work normally to break down clots that have formed. Heparin is generally used for anticoagulation for the following conditions: ACS, e.g., NSTEMI AF DVT and PE Cardiopulmonary bypass for heart surgery. ECMO circuit for extracorporeal life support Hemofiltration Indwelling central or peripheral venous catheters extracorporeal membrane oxygenation (ECMO) is an extracorporeal technique of providing both cardiac and respiratory support oxygen to patients whose heart and lungs are so severely diseased or damaged that they can no longer serve their function.
Pharmaceutical-grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestine or bovine (cow) lung
Heparin binds to the enzyme inhibitor antithrombin III (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop. [15] The activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin. AT binds to a specific pentasaccharide sulfation sequence contained within the heparin polymer: GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S) The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition, however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin.The formation of a ternary complex between AT, thrombin, and heparin results in the inactivation of thrombin. For this reason, heparin's activity against thrombin is size-dependent, the ternary complex requiring at least 18 saccharide units for efficient formation. In contrast, anti-factor Xa activity requires only the pentasaccharide binding site. This size difference has led to the development of LMWHs and, more recently, to fondaparinux as pharmaceutical anticoagulants. Low-molecular-weight heparins and fondaparinux target anti-factor Xa activity rather than anti-thrombin (IIa) activity, with the aim of facilitating a more subtle regulation of coagulation and an improved therapeutic index. The chemical structure of fondaparinux is shown above. It is a synthetic pentasaccharide, whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and heparan sulfate. With LMWH and fondaparinux, there is a reduced risk of osteoporosis and HIT . Monitoring of the aPTT is also not required and does not reflect the anticoagulant effect, as APTT is insensitive to alterations in factor Xa. Danaparoid, a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate, can be used as an anticoagulant in patients that have developed HIT. Because danaparoid does not contain heparin or heparin fragments, cross-reactivity of danaparoid with heparin-induced antibodies is reported as less than 10%. The effects of heparin are measured in the lab by the partial thromboplastin time (aPTT), (the time it takes the blood plasma to clot).
Bolus dosing for UFH initiation IV varies considerably by condition being treated as does dose infusion rates. Facility should ensure that (1) ALL heparin IV boluses and infusion rate changes will have independent double check performed by two of the following –RN/MD/PA/NP/Pharmacist and (2) all facilities WILL use programmable infusion pumps for the administration of heparin.
Not all inclusive lists
Dose 1 mg for every 100 units of heparin
Heparin is a naturally occurring polysaccharide that inhibits coagulation, the process whereby thrombosis occurs (see Heparin: Mechanisms of action). Natural heparin consists of molecular chains of varying lengths, or molecular weights. Chains of varying molecular weights, from 5000 to over 40,000 Daltons, make up polydisperse pharmaceutical-grade heparin. [2] Heparin derived from natural sources, mainly porcine intestine or bovine lung, can be administered therapeutically to prevent thrombosis. However, the effects of natural, or unfractionated heparin can be difficult to predict. After a standard dose of unfractionated heparin, coagulation parameters must be monitored very closely to prevent over- or under-anticoagulation. Low-molecular-weight heparins (LMWHs), in contrast, consist of only short chains of polysaccharide. LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da. These are obtained by various methods of fractionation or depolymerisation of polymeric heparin.
Specifically limited to enoxaparin, other LMWHs are available (dalteparin & tinzaparin)
* Not available at all MTFs
LMWH Innohep (Tinzaparin) sc 4500 u (0.45 ml) 10000 u (0.5 ml) 14000 u (0.7 ml) 18000 u (0.9 ml) Clexane (Enoxaparine) iv, sc 20 mg (0.2 ml) 40 mg (0.4ml) 60 mg (0.6 ml) 80 mg (0.8 ml) Fraxiparine (Nadroparine Ca) iv , sc 2850 u (0.3 ml) 5700 u(0.6 ml) 7600 u (0.8ml) Differences from unfractionated heparin Differences from heparin (i.e. "unfractioned heparin") include: Average molecular weight: heparin is about 15 kDa and LMWH is about 4.5 kDa. [12] Less frequent subcutaneous dosing than for heparin for postoperative prophylaxis of venous thromboembolism. Once or twice daily subcutaneous injection for treatment of venous thromboembolism and in unstable angina instead of intravenous infusion of high dose heparin. No need for monitoring of the APTT coagulation parameter as required for high dose heparin. [13] Possibly a smaller risk of bleeding. Smaller risk of osteoporosis in long-term use. Smaller risk of heparin-induced thrombocytopenia, a potential side effect of heparin. The anticoagulant effects of heparin are typically reversible with protamine sulfate, while protamine's effect on LMWH is limited. Has less of an effect on thrombin compared to heparin, but about the same effect on Factor Xa.
The four Vitamin K dependent clotting factors are synthesized in the liver.
The Vitamin K dependent clotting factors are carboxylated in a reaction that is linked to the oxidation of the reduced form of the vitamin . The non carboxylated forms of these clotting factors are inactive because they cannot bind calcium. When Vitamin K is deficient, non-carboxylated prothrombin is secreted and this protein is non functional. Carboxylation of terminal glutamic acid side chains (known as the Glu to Gla conversion) allows the clotting factors to bind calcium which in turn bridges the clotting factors to phospholipid surfaces, a necessary requirement for their activity.
Inhibits vitamin K dependent pro-coagulation factors (II, VII, IX and X) Also inhibits protein C and S synthesis which is associated with pro-coagulability and reason for overlap with heparin therapy 24 hour decrease in Factor VIII, Protein C Followed by Factor IX on day 2, Factor X on day 3.5, Factor II on day 5
The relative contraindications for warfarin are listed on this slide. Warfarin crosses the placenta and is teratogenic in the first trimester, producing warfarin embryopathy in about 5% of exposed neonates. It is also fetopathic when used after the first trimester in an unknown (but much smaller) percentage of fetuses. Warfarin is contraindicated (relative or absolute) in patients with an increased risk of serious bleeding. The indication for warfarin should be reviewed carefully in patients with relative contraindications.
*many MTFs require orders to be rewritten periodically (i.e 3 days)
The major side effect of warfarin is hemorrhage. The factors that can influence the bleeding risk are shown on this slide; three of these potential risk factors, namely: the intensity of anticoagulation, concomitant use of other medications, and quality of management are controllable. The intensity of anticoagulation is an extremely important risk factor for adverse events. This is because warfarin, a narrow therapeutic index drug, has a small window of therapeutic effectiveness and dosing must be carefully managed. Such management is best achieved in the setting of an anticoagulation management service (anticoagulation clinic). The blue (or purple) toe syndrome consists of the development of blue or violaceous discoloration of one or more toes in the absence of obvious trauma, serious cold-induced injury, or disorders producing generalized cyanosis. The major general categories are: (1) decreased arterial flow, (2) impaired venous outflow, and (3) abnormal circulating blood.
*if available
The elderly are at special risk for bleeding because: 1) increased age is associated with an increased sensitivity to warfarin, therefore the elderly often require lower doses of warfarin to maintain their INR in the therapeutic range 2) they often have concomitant disorders that either influence their response to warfarin or expose them to the risk of bleeding 3) these disorders may require therapy with drugs that either interfere with the pharmacodynamics of warfarin or increase the risk of bleeding 4) increased age itself (due to increased vascular fragility) might be an independent risk factor for warfarin-associated bleeding. Because of an increased sensitivity to warfarin, comorbidity and increased drug interactions, the elderly require even more careful management of dose adjustment.In the case of intracranial hemorrhage, there may be a slight, but real increased risk in the very elderly regardless of the quality of management.
The prothrombin time (PT) is the test most commonly used to monitor warfarin dosing. The reliability of the result of the PT is influenced adversely by the variability in the sensitivity of thromboplastin reagents used by different laboratories. This problem has been markedly reduced by reporting the PT ratio as an International Normalized Ratio (INR).
The INR is a mathematical correction that normalizes the PT ratio by adjusting for the variability in the sensitivity of the different thromboplastins.
The INR is calculated by the formula shown on this slide. The ISI is the International Sensitivity Index. Each thromboplastin is assigned an ISI which reflects the sensitivity of the thromboplastin to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. By convention, the ISI of the reference thromboplastin is 1.0. The higher the ISI, the less sensitive the thromboplastin is to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. The next two slides provide an example of how the ISI (sensitivity) of the thromboplastin influences the PT ratio (PTR) and how the resulting variability is corrected by expressing the results as an INR.
Although the INR method of reporting represents a marked improvement over the PTR, it is not perfect. It is less reliable during the induction than the maintenance period, although still much more reliable than the PTR. It loses accuracy when insensitive thromboplastins (with a high ISI) are used. It is subject to incorrect assignments of the ISI value by the manufacturer, and loses reliability if the control PT mean is calculated incorrectly. The solutions to these four problems are listed in the right hand column of the slide. Three of the problems are solved or reduced in magnitude by selecting thromboplastins with low ISI values.
When short-term heparin followed by long-term warfarin are used, both anticoagulants can be started simultaneously. Heparin should be continued for a minimum of four days because the peak antithrombotic effect of warfarin is delayed for about 96 hours, independently of the INR, until Factor II (prothrombin is reduced). Heparin can be discontinued after a minimum of four days when the INR reaches the therapeutic range.
The signs of warfarin overdosage are listed on this slide. Hemorrhagic complications from warfarin therapy are more likely to occur with excessive degrees of anticoagulation, but even with an INR in the therapeutic range, bleeding can occur. Because of the likelihood of finding an underlying lesion in an individual who has gastrointestinal bleeding or significant genito-urinary bleeding in the face of therapeutic levels of anticoagulation, one is advised to consider and evaluate for underlying abnormalities predisposing to the bleeding. The return on such evaluations in the face of an excessive degree of anticoagulation diminishes, and one must use judgement whether or not to pursue an evaluation.
These indications and recommended intensities of treatment are derived from the Fifth American College of Chest Physicians Consensus Conference (1998). For most indications a therapeutic range of 2.0 to 3.0 is recommended. A higher INR range of 2.5 to 3.5 is recommended for parents with mechanical prosthetic valves and post myocardial infarction and for some patients with antiphospholipid syndrome and a history of thrombosis.
