低分子肝素(英文)(學習資料)課件

Low-Molecular-WeightHeparin

and

UnfractionatedHeparin5/001MedSLow-Molecular-WeightHeparin

aTheCoagulationCascadeCentraltothecoagulationcascadeisthegenerationofthrombin(factorIIa)thrombinisgeneratedfromprothrombinbytheactionofactivatedfactorX(Xa)thrombinthenactsonfibrinogentogeneratefibrinclot5/982MedSTheCoagulationCascadeCentralCoagulationCascadeXIIaXIaIXaIntrinsicPathway(surfacecontact)XaExtrinsicPathway(tissuefactor)VIIaThrombin(IIa)Thrombin-FibrinClotaPTTPTHeparin/LMWH

(AT-IIIdependent)Hirudin/Hirulog

(directantithrombin)CourtesyofVTI5/983MedSCoagulationCascadeXIIaXIaIXaITHROMBOSISCollagenXIa TissueFactorIXaPlateletClumpingThrombusFormationThrombusGrowthHEMOSTASISTissueFactor& CollagenPlateletAggregationPlatelet-richHemostaticPlugXaFluidThrombinHEPHEP&HIRHeparinInhibitsHemostasis5/984MedSTHROMBOSISHEMOSTASISXaHEPHEP&TheProcoagulantStateinThrombolysisAmplificationVascularInjuryActivationofPlateletsAndCoagulationXaThrombin(IIa)5/985MedSTheProcoagulantStateinThroLow-molecular-weightheparinUH(mw3k-30k)isaheterogeneousmixtureofpolysacchridechains(glycosaminoglycans)LMWH(mw5k)isobtainedbyalkalinedegradationofheparinbenzylesterLMWHmoleculesareenrichedwithshortchainswithhigheranti-Xa:IIaratio5/986MedSLow-molecular-weightheparinUHMechanismofActionBothUHandLMWHexerttheiranticoagulationactivitybycatalyzingantithrombin

(ATorATIII)catalyzedATisacceleratedinitsinactivationofthecoagulationenzymesthrombin(factorIIa)andfactorXlongsaPTT5/987MedSMechanismofActionBothUHandTherearetwoheparin-cofactors,Antithrombin(AT)andHeparinCo-factorII(HCII).ATisaneffectiveantithrombinbutHCIIisaveryweakantithrombinATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSC5/988MedSTherearetwoheparin-cofactorATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSCHeparinhasahigheraffinityforATthanforHCIIandthereismoreATinplasmathanHCII5/989MedSATHCII++++InteractionofHepaATFreeThrombinAntithrombinandFreeThrombinATalonedoesnotinactivate

free-thrombinThrombinHFSC5/9810MedSATFreeThrombinAntithrombinanHeparinbindstoantithrombinandincreasestherateofthrombininactivationATHeparinInactivationofThrombinby

Heparin-ATComplexesThrombinHFSC5/9811MedSHeparinbindstoantithrombinATFibrin-BoundThrombinTherateatwhichATinactivatesfibrin-boundthrombinisreduced50-foldEffectofAntithrombinon

Fibrin-BoundThrombinThrombinHFSC5/9812MedSATFibrin-BoundThrombinTheratInactivationofThrombinby

Heparin-ATComplexesWhenthrombinbindstofibrin,itbecomesresistanttoinactivationbyheparin.ATHeparinFibrinThrombinHFSC5/9813MedSInactivationofThrombinby

HMechanismofActionSummaryCatalyzesATIIISpecificforfluid-phasethrombinProlongsaPTTbyinactivatingthrombinandblockingXageneration5/9814MedSMechanismofActionSummary5/98Differencesin

MechanismofActionAnysizeofheparinchaincaninhibittheactionoffactorXabybindingtoantithrombin(AT)Incontrast,inordertoinactivatethrombin(IIa),theheparinmoleculemustbelongenoughtobindbothantithrombinandthrombin<halfthechainsofLMWHarelongenough5/9815MedSDifferencesin

MechanismofAATUnfractionatedHeparinDifferentialinhibitoryactivityagainst

factorXaandIIaactivityThrombin(IIa)HFSCATLMWHThrombin(IIa)HFSCBybindingtoAT,mostUHandLMWHcaninhibitXaactivity.

FewerthanhalfthechainsofLMWHareofsufficientlengthtoalsobindfactorIIa,thereforehasdecreasedanti-IIaactivity.5/9816MedSATUnfractionatedHeparinDifferLow-Molecular-WeightHeparins

Anti-FacotrXa:Anti-FactorIIaRatiosAgent Trade Xa:IIa MolWt(d)Enosaparin Lovenox 3.8:1 4,200Dalteparin Fragmin 2.7:1 6,000Ardeparin Normiflo 1.9:1 6,000Nadroparin 3.6:1 4,500Reviparin 3.5:1 4,000Tinzaparin 1.9:1 4,5005/9817MedSLow-Molecular-WeightHeparins

AdvantagesofLMWHoverUHDecreased“heparinresistance”pharmacokineticsofUHareinfluencedbyitsbindingstoplasmaprotein,endothelialcellsurfaces,macrophages,andotheracutephasereactantsLMWHhasdecreasedbindingtononanticoagulant-relatedplasmaproteins5/9818MedSAdvantagesofLMWHoverUHDecrAdvantagesofLMWHoverUHNoneedforlaboratorymonitoringwhengivenonaweight-adjustedbasis,theLMWHanticoagulantresponseispredictableandreproducibleHigherbioavailability-90%vs30%Longerplasmahalf-life4to6hoursvs0.5to1hourrenal(slower)vshepaticclearance5/9819MedSAdvantagesofLMWHoverUHNonAdvantagesofLMWHoverUHLessinhibitionofplateletfunctionpotentiallylessbleedingrisk,butnotshowninclinicaluseLowerincidenceofthrombocytopeniaandthrombosis(HITsyndrome)lessinteractionwithplateletfactor4fewerheparin-dependentIgGantibodies5/9820MedSAdvantagesofLMWHoverUHLessMonitoringofLMWHUnnecessaryinmajorityofpatientsMaybeusefulinspecificinstancesrenalinsufficiency(creatinine>2.0mg/dl)obesepatientswithaltereddrugpKmajorbleedingriskfactorsaPTTnotuseful-lowanti-IIaactivityanti-factorXaassayismoreappropriate,butnotwidelyavailable5/9821MedSMonitoringofLMWHUnnecessaryESSENCETrial

EfficacyandSafetyofSubcutaneous

Enoxaparininnon-Q-WaveCoronaryEventsStudyArandomizedstudycomparingtheclinicalefficacyofUFHvsenoxaparinLMWHin3171patientswithrestanginaornon-Q-waveMIat30days,therewasarelativeriskreductionof15%-16%intherateofdeath,MI,orrefractoryischemiaascomparedtostandardheparinNEngJMed1997;337:447-4525/9822MedSESSENCETrial

EfficacyandSafESSENCEEnoxaparin1.0mg/kgq12hsubcutaneousUFH

5,000Ubolus+inf

aPTT55-85secUnstableAnginaNon-QWaveMIAcutePhasemin48h,max8Days30days

Enox HepIncidenceofdeath,MI,angina

14d 16.6%19.8%p=.019

30d 19.8%23.3%p=.016Minorbleeding

30d13.8%8.8%p<.001Majorbleeding

30d 6.5%7.0%NSDeathalone

14d2.2%2.3%NS

30d 2.9%3.6%NS5/9823MedSESSENCEEnoxaparinUFH

5,000UTIMI11B-StudyDesignEnoxaparin30mgIVbolus+1.0mg/kgq12hsubcutaneousUFH70U/kgIVbolus+15U/Kg/hUFHIVUnstableAnginaNon-QWaveMIAcutePhasemin72h,max8DaysChronicPhaseFixedDose<65kg >65kg40mg 60mgq12hFixedDoseplaceboq12h43days5/9824MedSTIMI11B-StudyDesignEnoxapaTIMI11B

LMWHinUnstableAngina4,021ptswithacutecoronarysyndromeTwotreatmentgroups:

UFH:70U/kgbolus15u/kg/hriv

LMWH:30mgbolus1mg/kgs.q.bidPrimaryendpoint

(death,MI,urgentrevascularization)

48-72hr 26%

14days 15% p<0.03Circulation1999;100:1593-16015/9825MedSTIMI11B

LMWHinUnstableAngiMeta-Analysis

ESSENCEandTIMI11BPrimaryendpoint

Death/MI/UrgentRevscularizationOddsratio RiskReduction p-valDay80.71 21% 0.02Day140.79 21% 0.0005Day430.80 20% 0.0006EuropeanSocietyofCardiology-August19985/9826MedSMeta-Analysis

ESSENCEandTIMIPrimaryEndpoint:Day43

Death/MI/UrgentRevasc5/9827MedSPrimaryEndpoint:Day43

DeatDifferenceBetweenLovenoxandHeparin Lovenox Heparin

Half-life(hr) 4.5 dose-dependent Anti-Xa:IIa 14:1 1:1 Molecularwt(avg) 4,500 15,000

Timetopeakactivity 3-5 2-4

Dosingunits mg IU5/9828MedSDifferenceBetweenLovenoxandEnoxaparininDVTProphylaxis

DOSAGE DURATION

inpatientsundergoing 30mgq12hSC averageduration:7to10days

hip-replacementsurgery initiate12-24hpostop upto14days 40mgqdSC

initiated12h(3)preop

extendedprophylaxisin 40mgqdSC 3weekspostdischarge

hipreplacement

inpatientsundergoing 30mgq12hSC averageduration:7to10days

knee-replacementsurg initiate12-24hpostop

inpatientsundergoing 40mgqdSC averageduration:7to10days

abdominalsurgery initiate2hpreop 4/0029MedSEnoxaparininDVTProphylaxis EnoxaparininTreatmentof

inacuteDVTwithorwithoutPE

DOSAGE DURATION

Forpatientswhocanbe 1mgq12hSC continueLOVENOXfora

treatedathomeforacute initiatewarfarinsodium minimalof5daysanduntil

DVTwithoutPE therapywhenappropriate atherapeuticoralanticoagulant (usuallywithin72hof effecthasbeenachieved(INR

Lovenoxadministration) 2.0to3.0).

averageduration:7days

Forhospitalizedpatients 1.5mg/kgqdSCatthe

withacuteDVTwithor sametimeeverydayor

withoutPE 1mg/kgq12hSC

4/0030MedSEnoxaparininTreatmentof

inEnoxaparinforUAandnon-QMI

DOSAGE DURATION

Forthepreventionof 1mg/kgq12hSC minimum2days;usualduration

ischemiccomplications withoralaspirintherapy oftherapy:2to8days

ofunstableanginaand (100to325mgoncedaily)

non-Q-wavemyocardial

infarction(MI)when

concurrentlyadministered

withaspirin4/0031MedSEnoxaparinforUAandnon-QMIEconomicAssessmentofLMWHvsUFH

ResultsfromtheESSENCETrail

enoxaparinheparin

Needfor

coronaryangioplasty(initial) 15% 20% p=.04

coronaryangioplasty(30d) 18% 22% p=.08

diagnosticcath(30d) 57% 63% p=.04

Initialhospitalization

meandrugcostinU.S.* $155 $80

meantotalcostofcare $11,857 $12,620

meandurationoftreatment2.3days

mutidosevialenoxaparin-1mg/kgat$0.38/mgCirculation1998;97:1702-17075/9832MedSEconomicAssessmentofLMWHvsReferencesLow-molecularweightheparins.

WeitzJI.NEngJMed1997;337:688-698.Biochemistryandpharmacologyoflowmolecularweightheparin.

RosenbergRD.SeminHematol1997;34(suppl4):2-8.Heparin-inducedthrombocytopeniainpatientstreatedwithlow-molecular-weightheparinorunfractionaedheparin.

WarkentinTE,LevineMN,HirshJ,HorsewoodP,RobertsRS,GentM,etal.NEnglJMed1995;332:1330-1335.UseofLMWHinthetreatmentofvenousthromboembolicdisease.

LitinSC,HeitJA,MeesKA,fortheThrombophiliaCenterInvestigators.

MayoClinProc1998;73:545-551.5/9833MedSReferencesLow-molecularweightLow-Molecular-WeightHeparin

and

UnfractionatedHeparin5/0034MedSLow-Molecular-WeightHeparin

aTheCoagulationCascadeCentraltothecoagulationcascadeisthegenerationofthrombin(factorIIa)thrombinisgeneratedfromprothrombinbytheactionofactivatedfactorX(Xa)thrombinthenactsonfibrinogentogeneratefibrinclot5/9835MedSTheCoagulationCascadeCentralCoagulationCascadeXIIaXIaIXaIntrinsicPathway(surfacecontact)XaExtrinsicPathway(tissuefactor)VIIaThrombin(IIa)Thrombin-FibrinClotaPTTPTHeparin/LMWH

(AT-IIIdependent)Hirudin/Hirulog

(directantithrombin)CourtesyofVTI5/9836MedSCoagulationCascadeXIIaXIaIXaITHROMBOSISCollagenXIa TissueFactorIXaPlateletClumpingThrombusFormationThrombusGrowthHEMOSTASISTissueFactor& CollagenPlateletAggregationPlatelet-richHemostaticPlugXaFluidThrombinHEPHEP&HIRHeparinInhibitsHemostasis5/9837MedSTHROMBOSISHEMOSTASISXaHEPHEP&TheProcoagulantStateinThrombolysisAmplificationVascularInjuryActivationofPlateletsAndCoagulationXaThrombin(IIa)5/9838MedSTheProcoagulantStateinThroLow-molecular-weightheparinUH(mw3k-30k)isaheterogeneousmixtureofpolysacchridechains(glycosaminoglycans)LMWH(mw5k)isobtainedbyalkalinedegradationofheparinbenzylesterLMWHmoleculesareenrichedwithshortchainswithhigheranti-Xa:IIaratio5/9839MedSLow-molecular-weightheparinUHMechanismofActionBothUHandLMWHexerttheiranticoagulationactivitybycatalyzingantithrombin

(ATorATIII)catalyzedATisacceleratedinitsinactivationofthecoagulationenzymesthrombin(factorIIa)andfactorXlongsaPTT5/9840MedSMechanismofActionBothUHandTherearetwoheparin-cofactors,Antithrombin(AT)andHeparinCo-factorII(HCII).ATisaneffectiveantithrombinbutHCIIisaveryweakantithrombinATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSC5/9841MedSTherearetwoheparin-cofactorATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSCHeparinhasahigheraffinityforATthanforHCIIandthereismoreATinplasmathanHCII5/9842MedSATHCII++++InteractionofHepaATFreeThrombinAntithrombinandFreeThrombinATalonedoesnotinactivate

free-thrombinThrombinHFSC5/9843MedSATFreeThrombinAntithrombinanHeparinbindstoantithrombinandincreasestherateofthrombininactivationATHeparinInactivationofThrombinby

Heparin-ATComplexesThrombinHFSC5/9844MedSHeparinbindstoantithrombinATFibrin-BoundThrombinTherateatwhichATinactivatesfibrin-boundthrombinisreduced50-foldEffectofAntithrombinon

Fibrin-BoundThrombinThrombinHFSC5/9845MedSATFibrin-BoundThrombinTheratInactivationofThrombinby

Heparin-ATComplexesWhenthrombinbindstofibrin,itbecomesresistanttoinactivationbyheparin.ATHeparinFibrinThrombinHFSC5/9846MedSInactivationofThrombinby

HMechanismofActionSummaryCatalyzesATIIISpecificforfluid-phasethrombinProlongsaPTTbyinactivatingthrombinandblockingXageneration5/9847MedSMechanismofActionSummary5/98Differencesin

MechanismofActionAnysizeofheparinchaincaninhibittheactionoffactorXabybindingtoantithrombin(AT)Incontrast,inordertoinactivatethrombin(IIa),theheparinmoleculemustbelongenoughtobindbothantithrombinandthrombin<halfthechainsofLMWHarelongenough5/9848MedSDifferencesin

MechanismofAATUnfractionatedHeparinDifferentialinhibitoryactivityagainst

factorXaandIIaactivityThrombin(IIa)HFSCATLMWHThrombin(IIa)HFSCBybindingtoAT,mostUHandLMWHcaninhibitXaactivity.

FewerthanhalfthechainsofLMWHareofsufficientlengthtoalsobindfactorIIa,thereforehasdecreasedanti-IIaactivity.5/9849MedSATUnfractionatedHeparinDifferLow-Molecular-WeightHeparins

Anti-FacotrXa:Anti-FactorIIaRatiosAgent Trade Xa:IIa MolWt(d)Enosaparin Lovenox 3.8:1 4,200Dalteparin Fragmin 2.7:1 6,000Ardeparin Normiflo 1.9:1 6,000Nadroparin 3.6:1 4,500Reviparin 3.5:1 4,000Tinzaparin 1.9:1 4,5005/9850MedSLow-Molecular-WeightHeparins

AdvantagesofLMWHoverUHDecreased“heparinresistance”pharmacokineticsofUHareinfluencedbyitsbindingstoplasmaprotein,endothelialcellsurfaces,macrophages,andotheracutephasereactantsLMWHhasdecreasedbindingtononanticoagulant-relatedplasmaproteins5/9851MedSAdvantagesofLMWHoverUHDecrAdvantagesofLMWHoverUHNoneedforlaboratorymonitoringwhengivenonaweight-adjustedbasis,theLMWHanticoagulantresponseispredictableandreproducibleHigherbioavailability-90%vs30%Longerplasmahalf-life4to6hoursvs0.5to1hourrenal(slower)vshepaticclearance5/9852MedSAdvantagesofLMWHoverUHNonAdvantagesofLMWHoverUHLessinhibitionofplateletfunctionpotentiallylessbleedingrisk,butnotshowninclinicaluseLowerincidenceofthrombocytopeniaandthrombosis(HITsyndrome)lessinteractionwithplateletfactor4fewerheparin-dependentIgGantibodies5/9853MedSAdvantagesofLMWHoverUHLessMonitoringofLMWHUnnecessaryinmajorityofpatientsMaybeusefulinspecificinstancesrenalinsufficiency(creatinine>2.0mg/dl)obesepatientswithaltereddrugpKmajorbleedingriskfactorsaPTTnotuseful-lowanti-IIaactivityanti-factorXaassayismoreappropriate,butnotwidelyavailable5/9854MedSMonitoringofLMWHUnnecessaryESSENCETrial

EfficacyandSafetyofSubcutaneous

Enoxaparininnon-Q-WaveCoronaryEventsStudyArandomizedstudycomparingtheclinicalefficacyofUFHvsenoxaparinLMWHin3171patientswithrestanginaornon-Q-waveMIat30days,therewasarelativeriskreductionof15%-16%intherateofdeath,MI,orrefractoryischemiaascomparedtostandardheparinNEngJMed1997;337:447-4525/9855MedSESSENCETrial

EfficacyandSafESSENCEEnoxaparin1.0mg/kgq12hsubcutaneousUFH

5,000Ubolus+inf

aPTT55-85secUnstableAnginaNon-QWaveMIAcutePhasemin48h,max8Days30days

Enox HepIncidenceofdeath,MI,angina

14d 16.6%19.8%p=.019

30d 19.8%23.3%p=.016Minorbleeding

30d13.8%8.8%p<.001Majorbleeding

30d 6.5%7.0%NSDeathalone

14d2.2%2.3%NS

30d 2.9%3.6%NS5/9856MedSESSENCEEnoxaparinUFH

5,000UTIMI11B-StudyDesignEnoxaparin30mgIVbolus+1.0mg/kgq12hsubcutaneousUFH70U/kgIVbolus+15U/Kg/hUFHIVUnstableAnginaNon-QWaveMIAcutePhasemin72h,max8DaysChronicPhaseFixedDose<65kg >65kg40mg 60mgq12hFixedDoseplaceboq12h43days5/9857MedSTIMI11B-StudyDesignEnoxapaTIMI11B

LMWHinUnstableAngina4,021ptswithacutecoronarysyndromeTwotreatmentgroups:

UFH:70U/kgbolus15u/kg/hriv

LMWH:30mgbolus1mg/kgs.q.bidPrimaryendpoint

(death,MI,urgentrevascularization)

48-72hr 26%

14days 15% p<0.03Circulation1999;100:1593-16015/9858MedSTIMI11B

LMWHinUnstableAngiMeta-Analysis

ESSENCEandTIMI11BPrimaryendpoint

Death/MI/UrgentRevscularizationOddsratio RiskReduction p-valDay80.71 21% 0.02Day140.79 21% 0.0005Day430.80 20% 0.0006EuropeanSocietyofCardiology-August19985/9859MedSMeta-Analysis

ESSENCEandTIMIPrimaryEndpoint:Day43

Death/MI/UrgentRevasc5/9860MedSPrimaryEndpoint:Day43

DeatDifferenceBetweenLovenoxandHeparin Lovenox Heparin

Half-life(hr) 4.5 dose-dependent Anti-Xa:IIa 14:1 1:1 Molecularwt(avg) 4,500 15,000

Timetopeakactivity 3-5 2-4

Dosingunits mg IU5/9861MedSDifferenceBetweenLovenoxandEnoxaparininDVTProphylaxis

DOSAGE DURATION

inpatientsundergoing 30mgq12hSC averageduration:7to10days

hip-replacementsurgery initiate12-24hpostop upto14days 40mgqdSC

initiated12h(3)preop

extendedprophylaxisin 40mgqdSC 3weekspostdischarge

hipreplacement

inpatientsundergoing 30mgq12hSC averageduration:7to10days

knee-replacementsurg initiate12-24hpostop

inpatientsundergoing 40mgqdSC averageduration:7to10days

abdominalsurgery initiate2hpreop 4/0062MedSEnoxaparininDVTProphylaxis Enox