低分子肝素英文

5/981TheCoagulationCascadeCentraltothecoagulationcascadeisthegenerationofthrombin(factorIIa)thrombinisgeneratedfromprothrombinbytheactionofactivatedfactorX(Xa)thrombinthenactsonfibrinogentogeneratefibrinclot第1頁/共32頁5/982CoagulationCascadeXIIaXIaIXaIntrinsicPathway(surfacecontact)XaExtrinsicPathway(tissuefactor)VIIaThrombin(IIa)Thrombin-FibrinClotaPTTPTHeparin/LMWH

(AT-IIIdependent)Hirudin/Hirulog

(directantithrombin)CourtesyofVTI第2頁/共32頁5/983THROMBOSISCollagenXIa TissueFactorIXaPlateletClumpingThrombusFormationThrombusGrowthHEMOSTASISTissueFactor& CollagenPlateletAggregationPlatelet-richHemostaticPlugXaFluidThrombinHEPHEP&HIRHeparinInhibitsHemostasis第3頁/共32頁5/984TheProcoagulantStateinThrombolysisAmplificationVascularInjuryActivationofPlateletsAndCoagulationXaThrombin(IIa)第4頁/共32頁5/985Low-molecular-weightheparinUH(mw3k-30k)isaheterogeneousmixtureofpolysacchridechains(glycosaminoglycans)LMWH(mw5k)isobtainedbyalkalinedegradationofheparinbenzylesterLMWHmoleculesareenrichedwithshortchainswithhigheranti-Xa:IIaratio第5頁/共32頁5/986MechanismofActionBothUHandLMWHexerttheiranticoagulationactivitybycatalyzingantithrombin

(ATorATIII)catalyzedATisacceleratedinitsinactivationofthecoagulationenzymesthrombin(factorIIa)andfactorXlongsaPTT第6頁/共32頁5/987Therearetwoheparin-cofactors,Antithrombin(AT)andHeparinCo-factorII(HCII).ATisaneffectiveantithrombinbutHCIIisaveryweakantithrombinATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSC第7頁/共32頁5/988ATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSCHeparinhasahigheraffinityforATthanforHCIIandthereismoreATinplasmathanHCII第8頁/共32頁5/989ATFreeThrombinAntithrombinandFreeThrombinATalonedoesnotinactivate

free-thrombinThrombinHFSC第9頁/共32頁5/9810HeparinbindstoantithrombinandincreasestherateofthrombininactivationATHeparinInactivationofThrombinby

Heparin-ATComplexesThrombinHFSC第10頁/共32頁5/9811ATFibrin-BoundThrombinTherateatwhichATinactivatesfibrin-boundthrombinisreduced50-foldEffectofAntithrombinon

Fibrin-BoundThrombinThrombinHFSC第11頁/共32頁5/9812InactivationofThrombinby

Heparin-ATComplexesWhenthrombinbindstofibrin,itbecomesresistanttoinactivationbyheparin.ATHeparinFibrinThrombinHFSC第12頁/共32頁5/9813MechanismofActionSummaryCatalyzesATIIISpecificforfluid-phasethrombinProlongsaPTTbyinactivatingthrombinandblockingXageneration第13頁/共32頁5/9814Differencesin

MechanismofActionAnysizeofheparinchaincaninhibittheactionoffactorXabybindingtoantithrombin(AT)Incontrast,inordertoinactivatethrombin(IIa),theheparinmoleculemustbelongenoughtobindbothantithrombinandthrombin<halfthechainsofLMWHarelongenough第14頁/共32頁5/9815ATUnfractionatedHeparinDifferentialinhibitoryactivityagainst

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

FewerthanhalfthechainsofLMWHareofsufficientlengthtoalsobindfactorIIa,thereforehasdecreasedanti-IIaactivity.第15頁/共32頁5/9816Low-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 4,500第16頁/共32頁5/9817AdvantagesofLMWHoverUHDecreased“heparinresistance”pharmacokineticsofUHareinfluencedbyitsbindingstoplasmaprotein,endothelialcellsurfaces,macrophages,andotheracutephasereactantsLMWHhasdecreasedbindingtononanticoagulant-relatedplasmaproteins第17頁/共32頁5/9818AdvantagesofLMWHoverUHNoneedforlaboratorymonitoringwhengivenonaweight-adjustedbasis,theLMWHanticoagulantresponseispredictableandreproducibleHigherbioavailability-90%vs30%Longerplasmahalf-life4to6hoursvs0.5to1hourrenal(slower)vshepaticclearance第18頁/共32頁5/9819AdvantagesofLMWHoverUHLessinhibitionofplateletfunctionpotentiallylessbleedingrisk,butnotshowninclinicaluseLowerincidenceofthrombocytopeniaandthrombosis(HITsyndrome)lessinteractionwithplateletfactor4fewerheparin-dependentIgGantibodies第19頁/共32頁5/9820MonitoringofLMWHUnnecessaryinmajorityofpatientsMaybeusefulinspecificinstancesrenalinsufficiency(creatinine>2.0mg/dl)obesepatientswithaltereddrugpKmajorbleedingriskfactorsaPTTnotuseful-lowanti-IIaactivityanti-factorXaassayismoreappropriate,butnotwidelyavailable第20頁/共32頁5/9821ESSENCETrial

EfficacyandSafetyofSubcutaneous

Enoxaparininnon-Q-WaveCoronaryEventsStudyArandomizedstudycomparingtheclinicalefficacyofUFHvsenoxaparinLMWHin3171patientswithrestanginaornon-Q-waveMIat30days,therewasarelativeriskreductionof15%-16%intherateofdeath,MI,orrefractoryischemiaascomparedtostandardheparinNEngJMed1997;337:447-452第21頁/共32頁5/9822ESSENCEEnoxaparin1.0mg/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%NS第22頁/共32頁5/9823TIMI11B-StudyDesignEnoxaparin30mgIVbolus+1.0mg/kgq12hsubcutaneousUFH70U/kgIVbolus+15U/Kg/hUFHIVUnstableAnginaNon-QWaveMIAcutePhasemin72h,max8DaysChronicPhaseFixedDose<65kg >65kg40mg 60mgq12hFixedDoseplaceboq12h43days第23頁/共32頁5/9824TIMI11B

LMWHinUnstableAngina4,021ptswithacutecoronarysyndromeTwotreatmentgroups:

UFH:70U/kgbolus15u/kg/hriv

LMWH:30mgbolus1mg/kgs.q.bidPrimaryendpoint

(death,MI,urgentrevascularization)

48-72hr 26%

14days 15% p<0.03Circulation1999;100:1593-1601第24頁/共32頁5/9825Meta-Analysis

ESSENCEandTIMI11BPrimaryendpoint

Death/MI/UrgentRevscularizationOddsratio RiskReduction p-valDay80.71 21% 0.02Day140.79 21% 0.0005Day430.80 20% 0.0006EuropeanSocietyofCardiology-August1998第25頁/共32頁5/9826PrimaryEndpoint:Day43

Death/MI/UrgentRevasc第26頁/共32頁5/9827DifferenceBetweenLovenoxandHeparin 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 IU第27頁/共32頁4/0028EnoxaparininDVTProphylaxis

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 第28頁/共32頁4/0029EnoxaparininTreatmentof

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

第29頁/共32頁4/0030EnoxaparinforUAandnon-QMI

DOSAGE DURATION

Forthepreventionof 1mg/kgq12hSC minimum2days;usualduration

ischemiccomplications withoralaspirintherapy oftherapy:2to8days

ofunstableanginaand (100to325mgoncedaily)

non-Q-wavemyocardial

infarction(MI)when

concurrentlyadministered

withaspirin第30頁/共32頁5/9831EconomicAssessmentofLMWHvsUFH

ResultsfromtheESSENCETrail

enoxaparinheparin

Needfor

coronaryang