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Monitoring the Traditional & theMonitoring the Traditional & the
New AnticoagulantsNew Anticoagulants
Michael J. Sanfelippo, M.S.Michael J. Sanfelippo, M.S.
Technical Director, Coagulation ServicesTechnical Director, Coagulation ServicesMarshfield LabsMarshfield Labs
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Anticoagulants to be DiscussedAnticoagulants to be Discussed
HeparinHeparin
WarfarinWarfarin
Low Molecular Weight heparinLow Molecular Weight heparin FonaparienuxFonaparienux
Direct Thrombin InhibitorDirect Thrombin Inhibitor
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Unfractionated Heparin ChemicalUnfractionated Heparin Chemical
CompositionComposition Sulfated glycosaminoglycanSulfated glycosaminoglycan
Polysaccharide chains with moleculr weights ofPolysaccharide chains with moleculr weights of
30,00030,000 100,000100,000 Chains alternating NChains alternating N--acetylglucosamine andacetylglucosamine and
glucuronic acidglucuronic acid
Purified heparin polysaccharide chains of 3,000Purified heparin polysaccharide chains of 3,000 35,000 with average molecular weight of35,000 with average molecular weight of
12,00012,000
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Pharmacokinetics of HeparinPharmacokinetics of Heparin
Intravenous administrationIntravenous administration immediateimmediate
anticoagulation half life of one houranticoagulation half life of one hour
anticoagulant effect for 2anticoagulant effect for 2 6 hours6 hours Subcutaneous administrationSubcutaneous administration peakpeak
anticoagulation at 4 hours with effect up to 12anticoagulation at 4 hours with effect up to 12
hourshours
In high doses, most is excreted in the urineIn high doses, most is excreted in the urineunalteredunaltered
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Use of HeparinUse of Heparin
Immediate anticoagulantImmediate anticoagulant
Activity is variable requires monitoringActivity is variable requires monitoring
Used for initial treatment of DVT and PEUsed for initial treatment of DVT and PE Used in open heart surgeryUsed in open heart surgery
Used to cap intravenous linesUsed to cap intravenous lines
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Factors Affecting AnticoagulantFactors Affecting Anticoagulant
EffectEffect Level of AntithrombinLevel of Antithrombin
Heparin binding to acute phase proteinsHeparin binding to acute phase proteins
Release of platelet factor 4Release of platelet factor 4
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Monitoring HeparinMonitoring Heparin
Therapeutic range 0.3Therapeutic range 0.3 0.7 units/ml0.7 units/ml
Specific heparin assay, inhibition of XaSpecific heparin assay, inhibition of Xa
measured with chromogenic substratemeasured with chromogenic substrateAPTTAPTT
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Establishment of Therapeutic RangeEstablishment of Therapeutic Range
for APTTfor APTT
BrillBrill--Edwards MethodEdwards Method Measure heparin level in at least 30 patients on heparin only.Measure heparin level in at least 30 patients on heparin only.
Do APTTs on all specimensDo APTTs on all specimens
Calculate dose response curve by regression analysisCalculate dose response curve by regression analysis Therapeutic range is APTT range that corresponds to 0.3Therapeutic range is APTT range that corresponds to 0.3
0.7 units/ml0.7 units/ml
Determined from dose response curve using regressionDetermined from dose response curve using regressionanalysisanalysis
Problems for small hospitalProblems for small hospital Getting enough patientsGetting enough patients
Doing heparin assayDoing heparin assay
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Example of BrillExample of Brill--Edwards MethodEdwards MethodSpecimenSpecimen APTTAPTT HeparinHeparin
11 2525 0.150.15
22 4545 0.380.38
33 5555 0.450.4544 8888 0.850.85
55 7575 0.700.70
66 6565 0.550.55
77 3535 0.250.25
88 4747 0.350.35
99 6868 0.720.72
1010 9898 0.920.92
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BrillBrill--Edwards cont . . .Edwards cont . . .
APTT at 0.30 unitsAPTT at 0.30 units 47 sec47 sec
APTT at 0.7 unitAPTT at 0.7 unit 75 sec75 sec
Thus therapeutic range is 47Thus therapeutic range is 47 75 sec approximate75 sec approximate
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Specific Heparin AssaySpecific Heparin Assay
Based on inhibition of XaBased on inhibition of Xa
Heparin forms complex with antithrombinHeparin forms complex with antithrombin
(heparin(heparin--AT)AT) HeparinHeparin--At +XaAt +Xa ATAT--Xa + XaXa + Xa
Free Xa + chromogenicFree Xa + chromogenic substrate peptidesubstrate peptide
+Paranitroanaline+Paranitroanaline
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Heparin AssayHeparin Assay
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Adverse Effects ofProtamine SulfateAdverse Effects ofProtamine Sulfate
HemorrhageHemorrhage
Allergic reactionAllergic reaction
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Heparin Induced ThrombocytopeniaHeparin Induced Thrombocytopenia
Type I Platelet count drops slightly but returnsType I Platelet count drops slightly but returns
to normal while heparin is continuedto normal while heparin is continued--notnotantibody mediatedantibody mediated
Type II Severe antibody mediatedType II Severe antibody mediatedthrombocytopenia with life threatening arterialthrombocytopenia with life threatening arterial
and venous thrombosis if heparin is continuedand venous thrombosis if heparin is continued
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Heparin Induced ThrombocytopeniaHeparin Induced Thrombocytopenia
Type IIType II Potentially fatal complication of heparin therapyPotentially fatal complication of heparin therapy
due to the development of a heparin dependentdue to the development of a heparin dependentantibody against platelet factor 4antibody against platelet factor 4
Thrombocytopenia results from activation ofThrombocytopenia results from activation ofplatelets by complex of IgG, heparin, andplatelets by complex of IgG, heparin, and
platelet factor 4platelet factor 4
Platelet activation causes release of ADP whichPlatelet activation causes release of ADP whichcauses platelet aggregate formationcauses platelet aggregate formation
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Diagnostic Features of HIT Type IIDiagnostic Features of HIT Type II
Platelet count of less than 100,000/mmPlatelet count of less than 100,000/mm33 oror
count of less that 50% of the platelet countcount of less that 50% of the platelet countbefore heparin was startedbefore heparin was started
Occurs 5Occurs 5 12 days after heparin is started12 days after heparin is started
Abnormal results in tests for antibody to plateletAbnormal results in tests for antibody to platelet
factor 4 or heparin mediated platelet activationfactor 4 or heparin mediated platelet activation
Occurrence of arterial or venous thrombusOccurrence of arterial or venous thrombus
formation while on heparinformation while on heparin
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Tests for HIT Type IITests for HIT Type II
Elisa assay for antibody to platelet factor 4Elisa assay for antibody to platelet factor 4
Release of radioRelease of radio--labeled serotonin from normallabeled serotonin from normal
donor plateletsdonor platelets Daily platelet counts recommended for allDaily platelet counts recommended for all
patients on heparinpatients on heparin
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Treatment of HITTreatment of HIT Type IIType II
Stop heparinStop heparin
Use direct thrombin inhibitorsUse direct thrombin inhibitors
ArgatrobanArgatroban Lepiruden (RefludenLepiruden (Refluden))
Warfarin is contraindicatedWarfarin is contraindicated
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Low Molecular WeightLow Molecular Weight
HeparinHeparin
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Low Molecular Weight HeparinLow Molecular Weight Heparin
Made by enzymatic or chemicalMade by enzymatic or chemical
depolymerizationdepolymerization
Lower molecular weight 4,000Lower molecular weight 4,000 5,0005,000 Loss of most anti IIa activity but retain anti XaLoss of most anti IIa activity but retain anti Xa
Predicable anticoagulant activityPredicable anticoagulant activity
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Administration and Monitoring LowAdministration and Monitoring Low
Molecular Weight HeparinsMolecular Weight Heparins Given subcutaneouslyGiven subcutaneously
Peak level at 4 hours post injectionPeak level at 4 hours post injection
Half life of 4.5 hours with significant activity atHalf life of 4.5 hours with significant activity at12 hours12 hours
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Laboratory Monitoring LowLaboratory Monitoring Low
Molecular Weight HeparinMolecular Weight Heparin Usually not requiredUsually not required
Assayed by inhibition of Xa using aAssayed by inhibition of Xa using a
chromogenic substratechromogenic substrate Same assay as unfractionated heparin butSame assay as unfractionated heparin but
different calibratordifferent calibrator
APTT not reliable but may be slightly prolongedAPTT not reliable but may be slightly prolonged
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Conditions Requiring Monitoring ofConditions Requiring Monitoring of
Low Molecular Weight Heparin
Low Molecular Weight Heparin
Patients with renal insufficiencyPatients with renal insufficiency
Exceptionally large or small patientsExceptionally large or small patients
Newborn and childrenNewborn and children
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Low Molecular Weight Heparins inLow Molecular Weight Heparins in
CommonU
seCommonU
se Enoxaparin (LovenoxEnoxaparin (Lovenox))
Daltaparin (FragminDaltaparin (Fragmin))
Both calibrated against the same standardBoth calibrated against the same standard
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WarfarinWarfarin
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Action of WarfarinAction of Warfarin
Inhibits vitamin K epoxide reductaseInhibits vitamin K epoxide reductase
Prevents attachment of glutamic acid residues toPrevents attachment of glutamic acid residues to
factors II, VII, IX, X, protein C, and proteinS
factors II, VII, IX, X, protein C, and proteinS
Glutamic acid residues necessary for factor toGlutamic acid residues necessary for factor tobind to catalytic phospholipid surfacesbind to catalytic phospholipid surfaces
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Methods of MonitoringMethods of Monitoring
Accepted method is one stage prothrombin timeAccepted method is one stage prothrombin time
Assay of factor X with chromogenic substrateAssay of factor X with chromogenic substrate
for special conditionsfor special conditionsTraditional clotting assay of factor XTraditional clotting assay of factor X
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HalfHalf--Lives of Vitamin K DependentLives of Vitamin K Dependent
F
actorsF
actorsIIII 60 Hours60 Hours
VIIVII 44 6 Hours6 Hours
IXIX 2020 24 Hours24 Hours
XX 4848 72 Hours72 Hours
Protein CProtein C 8 Hours8 Hours
Protein SProtein S 30 Hours30 Hours
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Monitoring Warfarin withMonitoring Warfarin with
Prothrombin TimeP
rothrombin Time Reported as International Normalized RationReported as International Normalized Ration
(INR)(INR)
Reporting as clotting time in seconds only is notReporting as clotting time in seconds only is notacceptableacceptable
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INRINR
Calculated by the formalaCalculated by the formala
INR = Patient Time (sec)/Normal Mean Time(sec) ISCINR = Patient Time (sec)/Normal Mean Time(sec) ISC
Where ISC = International Sensitivity IndexWhere ISC = International Sensitivity Index
Test Plasma Time (sec)
Mean Normal Plasma TimeINR
ISI
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Use of the Chromogenic Factor XUse of the Chromogenic Factor X
AssayAssay Patients with the lupus anticoagulantPatients with the lupus anticoagulant
Patients with abnormal fibrinogen and problemPatients with abnormal fibrinogen and problem
in detection of fibrin endpointin detection of fibrin endpointTherapeutic range 43% to 17% correspondes toTherapeutic range 43% to 17% correspondes to
INR 2.0INR 2.0 3.53.5
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The Assay ofFactor X with aThe Assay ofFactor X with a
ChromogenicS
ubstrateChromogenicS
ubstrate Factor X is activated by Russells Viper VenomFactor X is activated by Russells Viper Venom
and Ca++and Ca++
Factor Xa hydrolyses substrate (S
2765)Factor Xa hydrolyses substrate (S
2765)liberating paranitroanalineliberating paranitroanaline
Optical density read at 405 nmOptical density read at 405 nm--directly related todirectly related to
factor X concentrationfactor X concentration
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Effect ofLupus Anticoagulant onEffect ofLupus Anticoagulant on
Prothrombin TimeP
rothrombin Time May bind phospholipid in test reagentMay bind phospholipid in test reagent
May also bind prothrombinMay also bind prothrombin
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Case History ofPatient withCase History ofPatient with
AbnormalF
ibrinogenAbnormalF
ibrinogen 65 year old female with atrial fibrillation on65 year old female with atrial fibrillation on
warfarin for several years with good controlwarfarin for several years with good control
Had INR performed at a different lab with aHad INR performed at a different lab with avalue of > 11.0value of > 11.0
Warfarin stoppedWarfarin stopped
Warfarin restarted with INRs at original labWarfarin restarted with INRs at original lab
acceptableacceptable INR performed at different lab with > 11.0INR performed at different lab with > 11.0
againagain
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Case History cont . . .Case History cont . . .
Duplicate specimens drawnDuplicate specimens drawn
Original lab INR 1.3Original lab INR 1.3
Other lab INR > 11.0Other lab INR > 11.0
Chromogenic X 79% (Normal 65Chromogenic X 79% (Normal 65 165%)165%)
Thrombin time 21.6 sec (16.4Thrombin time 21.6 sec (16.4 20.7 sec)20.7 sec)
Fibrinogen 642 mg/dl (174Fibrinogen 642 mg/dl (174--442 mg/dl)442 mg/dl)
Fibrinogen antigen 750 mg/dl (180Fibrinogen antigen 750 mg/dl (180 310 mg/dl)310 mg/dl)
Reptilase time 16.1 sec (15.5Reptilase time 16.1 sec (15.5 19.0 sec)19.0 sec)
Similar to Fibrinogen LongmontSimilar to Fibrinogen Longmont
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Adverse Affects of WarfarinAdverse Affects of Warfarin
Bleeding, anticoagulation reversal by vitamin KBleeding, anticoagulation reversal by vitamin K
Tissue necrosisTissue necrosis
Occurs in patients with underlying protein C orSOccurs in patients with underlying protein C orSdeficiency prevented by giving small loading dose ofdeficiency prevented by giving small loading dose of
22 5 mg/day starting warfarin while patient is on5 mg/day starting warfarin while patient is onheparinheparin
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Effect ofUnfractionated Heparin onEffect ofUnfractionated Heparin on
INRINR Heparin can prolong the prothrombin timeHeparin can prolong the prothrombin time
(increase INR)(increase INR)
Most reagents now contain a heparin antagonistMost reagents now contain a heparin antagonistprotamine sulfate or polybreneprotamine sulfate or polybrene
Most reagents will neutralize up to 1.0 units/mlMost reagents will neutralize up to 1.0 units/ml
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FondaparinuxFondaparinux
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Chemistry and Action ofChemistry and Action of
F
ondaparinuxF
ondaparinuxA pentasaccharide with a molecular weight ofA pentasaccharide with a molecular weight of
1,728 daltons1,728 daltons
Anticoagulates by accelerating the binding ofAnticoagulates by accelerating the binding ofantithrombin to Xaantithrombin to Xa
Has no effect on thrombin bindingHas no effect on thrombin binding
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Therapeutic Levels for FondaparinuxTherapeutic Levels for Fondaparinux
Administered by subcutaneous injectionsAdministered by subcutaneous injections
Peak level at 3 hour post injectionPeak level at 3 hour post injection
Half life 14Half life 14 20 hours, once per day dosing20 hours, once per day dosing
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Fondaparinux Used for ProphylaxisFondaparinux Used for Prophylaxis
2.5 mg daily2.5 mg daily
Peak level 0.39Peak level 0.39 0.50 mg/L0.50 mg/L
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Fondaparinux Used for Treatment ofFondaparinux Used for Treatment of
Deep Venous Thrombosis orDeep Venous Thrombosis or
Pulmonary EmbolismPulmonary Embolism
50 kg body weight 5.0 mg once/day50 kg body weight 5.0 mg once/day
5050 100 kg body weight 7.5 mg/day100 kg body weight 7.5 mg/day
Over 100 kg body weight 10.0 mg/dayOver 100 kg body weight 10.0 mg/day
Anticipated peak plasma levels 1.20Anticipated peak plasma levels 1.20 1.26 mg/L1.26 mg/L
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Methods of MonitoringMethods of Monitoring
Common laboratory tests, prothrombin time andCommon laboratory tests, prothrombin time andactivated partial thromboplastin time are insensitive toactivated partial thromboplastin time are insensitive tofondaparinuxfondaparinux
Specific assay based on inhibition of Xa with calibrationSpecific assay based on inhibition of Xa with calibrationcurve using fondaparinuxcurve using fondaparinux
Monitoring generally not required due to theMonitoring generally not required due to thepredictability of the drugs anticoagulant actionpredictability of the drugs anticoagulant action
Should be monitored in patients with renal impairmentShould be monitored in patients with renal impairment
and elderly patients (over 75 years)and elderly patients (over 75 years) Should be monitored in patients less than 50 kg bodyShould be monitored in patients less than 50 kg body
weightweight
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Advantages ofFondaparinuxAdvantages ofFondaparinux
Long half lifeLong half life
Low incidence of HIT, may be used to treatLow incidence of HIT, may be used to treat
patient who have suffered HITpatient who have suffered HIT Generally doesnt require monitoringGenerally doesnt require monitoring
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ArgatrobanArgatroban
A small molecule molecular weight of 526A small molecule molecular weight of 526
Derived from arginineDerived from arginine
Inhibits by reversibly binding to thrombinInhibits by reversibly binding to thrombinindependent of antithrombinindependent of antithrombin
Half life of 39Half life of 39 51 minutes51 minutes
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Therapeutic Levels and MonitoringTherapeutic Levels and Monitoring
Given by continuous infusionGiven by continuous infusion
Monitor with activated partial thromboplastin timeMonitor with activated partial thromboplastin time(APTT)(APTT)
At 2 hour of infusion target APTT range is 1.5At 2 hour of infusion target APTT range is 1.5 3.03.0times baselinetimes baseline
ArgatrobanArgatrobanwill prolong prothrombin time (PT)will prolong prothrombin time (PT)
Use chromogenic assay factor X to monitor warfarinUse chromogenic assay factor X to monitor warfarinduring transition from argatroban to warfarinduring transition from argatroban to warfarin
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Drug Use and Adverse AffectsDrug Use and Adverse Affects
Primary use to treat patients with HITPrimary use to treat patients with HIT
Hemorrhage is the only major adverse affectHemorrhage is the only major adverse affect
No known antidoteNo known antidote
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Lepiruden (RefludenLepiruden (Refluden))
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Therapeutic Levels and MonitoringTherapeutic Levels and Monitoring
Monitored by APTTMonitored by APTT
General target range 1.5General target range 1.5 2.5 baseline APTT2.5 baseline APTT
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Adverse Affects ofLepirudenAdverse Affects ofLepiruden
HemorrhageHemorrhage
No known antidoteNo known antidote