Management of Bleeding in Patients Receiving Direct Oral Anticoagulants - UpToDate

2016.12.02.
ManagementofbleedinginpatientsreceivingdirectoralanticoagulantsUpToDate
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate
Managementofbleedinginpatientsreceivingdirectoralanticoagulants
Authors: DavidAGarcia,MD,MarkCrowther,MD,MSc
SectionEditors: LawrenceLKLeung,MD,MariaEMoreira,MD
DeputyEditor: JenniferSTirnauer,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Nov2016.|Thistopiclastupdated:Nov14,2016.
INTRODUCTIONTheuseofanyanticoagulantisassociatedwithanincreasedriskofbleeding,and
bleedingcomplicationscanbelifethreatening.Bleedingisespeciallyconcerningwiththedirectoral
anticoagulants(DOACs)becauseantidotesorspecificreversalagentsforsomeoftheDOACsarelacking.
Additionally,routinecoagulationtestscannotbeusedtodeterminethedegreeofanticoagulation,makingit
morechallengingtodeterminewhentheanticoagulanteffecthasresolved.
ThistopicdiscussesourapproachtomanagingbleedinginpatientsreceivingDOACs.Specificindicationsfor
theseagents,detailsofadministrationandmonitoring,andperioperativemanagementoftheseagentsare
presentedseparately.(See"Directoralanticoagulants:Dosingandadverseeffects"and"Atrialfibrillation:
Anticoagulanttherapytopreventembolization"and"Overviewofthetreatmentoflowerextremitydeepvein
thrombosis(DVT)"and"Perioperativemanagementofpatientsreceivinganticoagulants"and"Venous
thromboembolism:Initiationofanticoagulation(first10days)".)
TERMINOLOGYANDSITESOFACTIONTerminologyfororalanticoagulantshasbeeninfluxas
individualagentsbecomemorefamiliar(lessnew)andadditionalagentsbecomeavailable.Weusethe
followingterminology:
Directoralanticoagulants(DOACs)DOACsareoralmedicationsthatinhibitaspecificenzymeinthe
coagulationcascade.Aconsensusdocumentregardingterminologyfortheseagentshasbeen
publishedalthoughnosingletermemergedastheobviouslybestterm,DOACwaspreferredbythemost
expertssurveyed[1].Thesemedicationsarealsocalledtargetspecificoralanticoagulants(TSOACs),
oraldirectinhibitors(ODIs),orreferredtobytheirindividualnamesortheenzymetheyinhibit.Weprefer
toavoidtheterms"noveloralanticoagulant"and"new(er)oralanticoagulant"(NOAC)becauseovertime
eachagentceasestobenovelornew.Somecliniciansrefertothisgroupofagentsas"nonvitaminK
antagonistoralanticoagulants",toretaintheNOACacronym.
Availableagentsincludethosethatdirectlyinhibitthrombin(factorIIa)orfactorXa.Thepositionsofthese
enzymesinthecoagulationcascadeareillustratedinthefigure(figure1)anddiscussedindetail
separately.(See"Overviewofhemostasis".)
DabigatranDabigatran(Pradaxa)istheonlyoraldirectthrombininhibitoravailableforclinicaluse.
Parenteraldirectthrombininhibitorsincludeargatrobanandbivalirudintheseagentsarediscussed
separately.(See"Directoralanticoagulants:Dosingandadverseeffects",sectionon'Argatroban'
and"Directoralanticoagulants:Dosingandadverseeffects",sectionon'Parenteraldirectthrombin
inhibitors'.)
Rivaroxaban,apixaban,edoxabanRivaroxaban(Xarelto),apixaban(Eliquis),andedoxaban
(Lixiana,Savaysa)areoraldirectfactorXa("tena")inhibitors.Ofnote,thegenericnamesforthese
agentsinclude"Xaban"(eg,rivaroxaban,apixaban,edoxaban).
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OtheranticoagulantsalsoinhibitfactorsXaandthrombin,buttheireffectsareindirect.Theeffectsof
heparins(whichinhibitfactorXaandtoalesserextentthrombin)andfondaparinux(whichinhibitsfactor
Xa)aremediatedthroughantithrombin(AT).WarfarinreducesthesynthesisoffunctionalfactorsII
(prothrombin),VII,IX,andXitsanticoagulanteffectisduetoreducedabilitytogenerateactivethrombin,
ratherthananinhibitionofactivatedenzymes.
DegreeofbleedingBleedingisaspectrum,andbleedingthatisinitiallyminorcansometimesbecome
moresignificantorevenlifethreatening.Thus,clinicaljudgmentisrequiredinallcasesofbleedingto
determinetherisktothepatientandtheappropriatedegreeofconcernregardingwhetherthebleedingis
resolvingorworsening.
Wedefineserious/majorbleedingasbleedingthatispotentiallyassociatedwithsignificantbloodloss(eg,
gastrointestinal)requiringbloodtransfusionorbleedingintoacriticalclosedspace(eg,intracranial
bleeding,compartmentsyndrome).Majorbleedingmayalsoincludebleedingrequiringaninterventionfor
management(eg,surgery,interventionalradiologyprocedures,endoscopictreatments).Majorbleeding
hasasignificantriskofimmediatemorbidity,regardlessofthecause.Somemajorbleedingmaybelife
threatening.
Minor,butstillclinicallysignificant,bleedingincludesbleedingrequiringahealthcareassessmentorless
invasivetreatment,suchasseveremenorrhagia,ecchymosis,orepistaxis.Alltypesofbleedingare
importanttothepatienthowever,veryminorbleedingusuallywillnotrequireinterruptionofanticoagulant
therapy.
BLEEDINGRISKSFROMDOACsAllanticoagulantsincreasebleedingrisk.Aswithotheranticoagulants,
DOACsareassociatedwithalowoverallriskofmajorbleeding.However,aswithanyanticoagulant,life
threateningbleedingcanoccur.
ClinicaloutcomesOutcomesofDOACassociatedbleedingappearfavorablecomparedwithvitaminK
antagonists.Thiswasdemonstratedina2015metaanalysisthatincluded13randomizedtrials(over100,000
patients)[2].Thecasefatalityrateformajorbleedingwas7.6percentinpatientstakingaDOAC,compared
with11percentforpatientstakingwarfarin.Therewerereductionsintherelativeriskoffatalbleeding(RR
0.5395%CI0.430.64),cardiovascularmortality(RR0.8895%CI0.820.94),andallcausemortality(RR
0.9195%CI0.870.96).ThereducedcasefatalityrateinpatientswithmajorDOACassociatedbleedingis
likelyattributabletothereducedrateofintracerebralhemorrhage(ICH).
VTEAmetaanalysisofrandomizedtrialsinpatientswithVTEincluded10trials(almost38,000
patients)[3].InsixtrialsthatcomparedVTEtreatmentusingaDOACoravitaminKantagonist,fatal
bleedingwaslessfrequentinDOACtreatedcomparedwithvitaminKantagonisttreatedpatients(0.09
versus0.18percentRR0.5195%CI0.261.01).InthreetrialsofsecondaryVTEprevention,allcause
mortalitywaslowerwithDOACadministrationcomparedwithplacebo(0.41versus0.86percentRR
0.3895%CI0.180.79).
AtrialfibrillationAreviewofrandomizedtrialsthatcompareddabigatranwithwarfarininpatientswith
atrialfibrillationincludedfivetrials(over27,000patients)[4].The30daymortalitywaslowerwith
dabigatranthanwarfarin(9.1versus13.0adjustedpooledoddsratio[OR]0.6695%CI0.441.00).
Dabigatrantreatedpatientsalsohadshorteraveragestaysintheintensivecareunitcomparedwith
warfarintreatedpatients(1.6versus2.6nights).
PostmarketingsurveillancealsohasnotshownanincreasedriskofbleedingfatalitieswiththeDOACagents
comparedwithvitaminKantagonists[5].
RiskofbleedingTherelativebleedingriskswithDOACsversusotheranticoagulants(eg,warfarin,low
molecularweight[LMW]heparin)havebeenevaluatedinvariousclinicalsettings.Risksofbleedingfrom
DOACsaregenerallylowerorsimilartovitaminKantagonists,withsomelimitedexceptions(eg,higherriskof
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gastrointestinalbleedinginpatientsolderthan65yearsreceivingdabigatran150mgtwicedailycompared
withwarfarin)[6,7].
TheoverallriskofbleedingwithDOACsversusvitaminKantagonistswasreviewedinametaanalysisof12
randomizedtrialsthatincluded102,607patientswithatrialfibrillationorvenousthromboembolism[8].
ComparedwithvitaminKantagonists,DOACswereassociatedwithlowerrisksofmajorbleeding(relativerisk
[RR]0.7295%CI0.620.85),fatalbleeding(RR0.5395%CI0.430.64),andintracranialbleeding(0.43
95%CI0.370.50)majorgastrointestinalbleedingwasnotincreased(RR0.9495%CI0.751.99).Thelower
riskoffatalbleedingseenwithDOACsisnoteworthybecausenoantidotewasavailableintheclinicaltrials.
Thislowerriskoffatalbleedingevenintheabsenceofaspecificreversalagenthighlightstheimportanceof
consideringa"supportivecare"approachwhenmanagingapatientwithDOACassociatedbleeding.(See
'Overviewofmanagement'below.)
Importantly,however,cliniciansweighingtherisksandbenefitsofaspecificanticoagulantmusttakeinto
accountindividualpatientfactorsandthespecificanticoagulantunderconsiderationtheseindividualfactors
maynotbecapturedbymetaanalysesthatcombinedatafromtrialsthatuseddifferentagentsand/or
differentdoses.Thefollowingreportsillustratesomegeneralobservationsaboutbleedingrisksinsome
patientpopulations:
AtrialfibrillationDatafromrandomizedtrialsinpatientswithatrialfibrillation(RELY,ROCKETAF,
ARISTOTLE)suggestthattheratesofmajorbleedinginpatientsreceivingDOACs(dabigatran,
rivaroxaban,andapixaban,respectively)areontheorderof2to3percentperyear,andratesof
hemorrhagicstrokeareontheorderof0.1to0.5percentperyear(table1)[912].Comparedwith
bleedingratesinpatientsreceivingwarfarin,ratesofmajorbleedingaresimilarwithDOACs,andratesof
hemorrhagicstrokearelesswithDOACs.
Thislowerbleedingriskcomparedwithwarfarinhasbeenreplicatedinsome,butnotall,"realworld"
studies[6,13].However,thereductionintheriskofintracerebralhemorrhage(ICH)anddeathhasbeen
seenconsistently,witharelativeriskreductionforICHontheorderof60to70percentinmoststudies.
Asexamples:
DabigatranAdatabasereviewthatincludedover50,000patientstreatedwithdabigatranor
warfarinforatrialfibrillationfoundthatuseofdabigatranwasassociatedwithlowerrisksofbleeding
thanwarfarin(gastrointestinalhemorrhage:1.6versus3.5per100,000patientdaysintracranial
hemorrhage:0.8verus2.4per100,000patientdays)[6].However,thisanalysiswaslimitedbythe
likelyallocationoflowerriskpatientstodabigatranandhigherriskpatientstowarfarin.
Anotherdatabasereviewthatincluded134,414patientstreatedwithdabigatranorwarfarinforatrial
fibrillationandadjustedforpotentiallyconfoundingvariablesfoundratesofmajorbleedingwith
dabigatranandwarfarinof4.3and4.4per100patientyears,respectively[14].RatesofICHinthis
reviewfordabigatranandwarfarinwere0.24and0.73per100patientyears,andmortalityrates
were3.3and3.8per100personyears.Areviewof341patientsintheDresdenregistryfoundrates
ofmajorbleedingof2.88and0.86per100personyearsatthedabigatran110mgtwicedailyand
150mgtwicedailydoses,respectively[15].
RivaroxabanAdatabasereviewthatincluded27,467patientstreatedwithrivaroxabanforatrial
fibrillationreported496majorbleedingevents(incidence,2.86per100personyears)and14major
bleedingdeaths(0.08per100personyears)[16].Mostofthemajorbleedsweregastrointestinal(89
percent,versus8percentICH).Patientswithmajorbleedingwereslightlyolderandhadhigherrates
ofhypertension,coronaryarterydisease,heartfailure,andkidneydisease.
TherearenorandomizedtrialscomparingoneDOACwithanother,althoughobservationalstudiesmay
showdifferencesinbleedingwithdifferentDOACs[17].Wewouldnotmakeanychangeinourclinical
practicebasedonobservationalstudies.
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VenousthromboembolismPatientsreceivingDOACsforthetreatmentofvenousthromboembolism
(VTE)haveanoverallannualriskofmajorbleedingofapproximately1percent.Ametaanalysisoffive
randomizedtrialsthatincluded24,455patientswithVTEwhoweretreatedwithaDOACreported
absoluteannualrisksforfatalbleeding,nonfatalICH,andgastrointestinalbleedingof0.06,0.09,and
0.35percent,respectively[18].TheriskformajorbleedingamongDOACtreatedpatientswaslowerthan
thatforpatientstreatedwithwarfarin(RRofanymajorbleedingwithaDOACcomparedwithwarfarin:
0.5095%CI0.410.88).AnobservationalstudyperformedinDresden,whichincluded575patientswith
VTEtreatedwithrivaroxaban,reported4.1majorbleedingepisodesper100patientyears[19].
OlderpatientsSomestudieshavefoundagetobeanindependentriskfactorforanticoagulant
associatedbleeding(ie,theyhavefoundahigherriskofbleedingfromanticoagulationinoldercompared
withyoungerpatients)othershavenot[20].Highqualitydataontherelativeriskofbleedinginolder
versusyoungerpatientsreceivingDOACsarenotavailable.However,olderpatientsreceivingDOACsdo
notappeartohaveagreaterriskofbleedingcomparedwitholderpatientsreceivingotheranticoagulants.
Thiswasdemonstratedinametaanalysisofrandomizedtrialsthatincluded25,031individualsage75
yearsorolder(10trials)[21].Clinicallyrelevantormajorbleedingwassimilartocontrols,whichincluded
warfarin,lowmolecularweightheparin,orplacebo(oddsratio[OR]1.0295%CI0.731.43).
RenalfailureAlloftheDOACsaredependentonrenalclearancetosomedegree.Thus,theriskof
DOACassociatedbleedingmaybegreaterinpatientswithrenalfailure.Ifananticoagulantisrequiredin
ahospitalizedpatientwithimportantrenalinsufficiency,unfractionatedheparinshouldbeconsidered.For
ambulatorypatients,decisionsregardingwhethertoanticoagulateandwhichagenttousemustbalance
therisksofbleedingversusthrombosisthepropertiesoftheindividualanticoagulantsmustalsobe
considered.Amoredetaileddiscussionofthisissueispresentedseparately.(See"Managementof
thromboembolicriskinpatientswithatrialfibrillationandchronickidneydisease".)
CoexistinghemostaticdefectsAlthoughnotextensivelystudiedinpatientsreceivingDOACs,itis
expectedthatcoexistinghemostaticdefectsmayincreasebleedingrisk.Thesemayincludeinherited
bleedingdisordersor,morecommonly,acquiredconditionssuchastheuseofnonsteroidal
antiinflammatorydrugs(NSAIDs)oraspirin.Themagnitudeoftheeffectislikelytodependonthe
severityofthehemostaticdefect.
ThelargerandomizedtrialsofDOACsversuswarfarinforstrokepreventioninatrialfibrillationincludeda
significantnumberofpatientstakingconcomitantaspirin(usuallylessthan100mgdaily).Subgroup
analysesfromthesetrialsindicatethataddingchroniclowdoseaspirintoaDOACisassociatedwithan
approximatelytwofoldincreaseintheriskofmajorbleeding.Thesameeffectwasalsoassociatedwith
theadditionofaspirintowarfarin.Thisincreaseinbleedingsuggeststhatcoincidenttherapywitheither
aspirinoranNSAIDshouldonlybeundertakenafterassessingtherisksandbenefitsofthetherapyand
afterfullyinformingthepatientoftherisk.TheeffectofNSAIDsandaspirinonbleedingriskinpatients
anticoagulatedwithwarfarinisdiscussedseparatelysomeofthemechanisms(eg,antiplateleteffect,
gastrointestinaltoxicity)mayalsoapplytoDOACs(see"Managementofwarfarinassociatedbleedingor
supratherapeuticINR",sectionon'Otherriskfactorsforbleeding').
Additionaldataregardingbleedingratesincludingintracerebralbleedingandbleedinginolderadultsare
presentedseparately.(See"Riskofintracerebralbleedinginpatientstreatedwithanticoagulants"and
"Anticoagulationinolderadults",sectionon'Riskofbleeding'.)
PATIENTASSESSMENTTheappropriatemanagementofDOACassociatedbleedingdependsonrisk
stratificationfortheseverityofthebleeding,anticoagulationstatus,andunderlyingindicationforthe
anticoagulant(table2).
InitialassessmentWeinitiallyassesstheseverityofbleedingandthedegreeofhemostaticimpairment.
Thisincludesathoroughhistoryandcompletereviewofmedications.Wespecificallyaddressthefollowing
fromthehistory:
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Howsevereisthebleedingandwhereisitlocated?
Isthepatientactivelybleedingnow?
Whichagentisthepatientreceiving?
Whenwasthelastdoseofanticoagulantadministered?
Couldthepatienthavetakenanintentionalorunintentionaloverdoseoftheanticoagulant?
Doesthepatienthaveahistoryofrenalorhepaticdiseasethatmightcauseexcessiveanticoagulant
effectinthesettingofstandarddrugdosing?
Isthepatienttakingothermedication(s)thatcouldaffecthemostasis(eg,aspirin,clopidogrel)?
Doesthepatienthaveothercomorbiditiesthatcouldpromotebleeding(eg,liverdisease,uremia)?
AssessmentofbleedingMoreseverebleedingwillrequiremoreaggressiveinterventionsthanminor
bleeding.Bleedingisassessedaccordingtothesite,rateofhemorrhage,andamountofbloodloss.This
includesathoroughphysicalexaminationwithserialmeasurementofvitalsigns.Serialmeasurementofthe
hemoglobinlevelmaybeappropriateifthereisconcernaboutsignificantbloodlossofnote,afallin
hemoglobinlevelislikelytobedelayedwithacutemassivebloodloss.(See'Otherlimitedlaboratorytesting'
below.)
Imagingstudies(eg,computedtomographyscanningforintracranialorretroperitonealhemorrhage)and/or
endoscopytovisualizethebleedingsitemayalsoberequired.
Ofnote,manypatientspresentingwithminorbleeding,slowbloodloss,orsimpleanemiawithoutevidenceof
bleedingmaynotrequireDOACreversal.Giventheshorthalflivesofthesedrugs,evenshorttermbut
unneededinterruptionoftherapycouldresultinavoidablethrombosis.Occasionally,bleedingthatappears
significantinfactisnot(eg,someepistaxisorhemorrhoidalbleeds)insuchcases,observationandlocal
measuressuchasiceandpressuremayallowresolutionofthebleedingwithoutrequiringaggressive
treatmentsthatmightexposethepatienttotherisksofreversalstrategiesandpotentialthrombosisdueto
withdrawalofanticoagulants.
AssessmentofanticoagulationstatusThedegreeofanticoagulationisimportantbothforpredictingthe
courseofthebleedingepisodeandwhichinterventionswillberequired.Theanticoagulationstatusdepends
onthespecificagent,dose,timesincethelastdose,andrenal(andtoalesserextenthepatic)function.
IntervalsincelastdoseWeconsideranticoagulationtohaveresolvedfullyafterfivehalfliveshave
elapsedsincethelastdose.Weusethefollowinghalflivesforpatientswithnormalrenalfunction[22]:
Dabigatran12to17hoursfivehalfliveswillhaveelapsedbyday2.5to3.5afterthelastdose.
Rivaroxaban5to9hoursfivehalfliveswillhaveelapsedbyday1to2afterthelastdose.
Apixaban8to15hoursfivehalfliveswillhaveelapsedbyday1.5to3afterthelastdose.
Edoxaban6to11hoursfivehalfliveswillhaveelapsedbyday1.3to2afterthelastdose.
RenalandhepaticfunctionThehalflivesoftheDOACsaredependentonrenal(andtoalesser
extenthepatic)functionthus,patientswithrenaland/orseverehepaticimpairmentmayhaveagreater
degreeand/ordurationofanticoagulationthanpatientswithnormalrenalandhepaticfunctionforagiven
doseand/orschedule.
DabigatranExcretionisapproximately80to85percentrenal.
RivaroxabanExcretionisapproximately35percentrenalseverehepaticimpairmentcouldresultinbio
accumulation.
ApixabanExcretionisapproximately25percentrenalseverehepaticimpairmentcouldresultinbio
accumulation.
EdoxabanExcretionisapproximately35percentrenalseverehepaticimpairmentcouldresultinbio
accumulation.
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CoagulationtestingRoutinecoagulationtestingisnotusedfordeterminingtheanticoagulationstatus
ofapatientreceivingaDOAC.Prolongedcoagulationtimescanbehelpfulindeterminingresidual
anticoagulanteffect(table3),butnormalcoagulationtestingcannotnecessarilybeusedasevidencethatthe
anticoagulanteffecthasresolvedortoeliminatetheneedforaggressiveinterventions.
Weperformthefollowingcoagulationtesting:
Prothrombintime/internationalnormalizedratio(PT/INR)
Activatedpartialthromboplastintime(aPTT)
Thrombinclottingtime(TT)inpatientswithsuspecteddabigatraneffect
Wegenerallytreatpatientswithnormalcoagulationtestingandpersistentbleedingasiftheyarestill
anticoagulated.IftherelevantlaboratoryhasdeterminedthatthePToraPTTisreliablyprolongedbythe
agentinquestion,anormalvaluemaybereassuringthisrequiresconsultationwithlaboratorypersonnel
regardinginstitutionspecifictestingthathasbeenvalidatedforuseinassessingDOACeffect.
DabigatranAlthoughwetreatpatientswithpersistentbleedinginthesettingofnormalcoagulation
testingasiftheyremainanticoagulated,anexceptionisapatientreceivingdabigatranwhohasanormal
TTweconsiderthissufficienttoeliminatethepossibilityofcontinueddabigatraneffect.However,theTT
isextremelysensitivetotheeffectsofdabigatranandcanbeprolongedevenbytrivialamountsofthe
drug.Ifavailable,acalibrateddiluteTTispreferablesinceitcorrelateslinearlywithdabigatran
concentration.
Rivaroxaban,apixaban,edoxabanSpecificassaysforantifactorXaactivityareavailableinmany
institutions,althoughonlyasmallnumberofclinicianswillhaveaccesstotheseassaysinatimely
fashion.TheabsenceofantifactorXaactivity,regardlessofhowanassayhasbeencalibrated,indicates
thatnoclinicallyrelevantantifactorXadrugeffectispresent.IncreasedantifactorXaactivitymayreflect
thepresenceofcontinuedantifactorXaanticoagulanteffecthowever,unlesstheassayusedhasbeen
calibratedforthespecificanticoagulantthepatientistaking,theamountofanticoagulanteffectpresent
cannotbereliablydetermined.Thus,itisimportanttoconsultwithlaboratorypersonnelregardinghow
theassaybehavesinthepresenceofeachofthedifferentfactorXainhibitors.
Wedonotusethromboelastography(TEG)orrelatedpointofcarecoagulationteststomanageDOAC
associatedbleeding.DOACshavebeendemonstratedtoaffecttheresultsofTEGandsimilartestshowever,
datacorrelatingthesetestswithdrugconcentration,clinicalbleeding,and/oranticoagulanteffectarelacking
[2327].
AdditionaltestsforDOACeffectareunderdevelopmentoravailableinsomelocations.Asanexample,the
HemoclotdirectthrombininhibitorassayisavailableforassessingdabigatraneffectinEuropeandCanada
[28].
Ofnote,patientsreceivingaDOACmayalsohavecoagulationabnormalitiesunrelatedtotheDOAC(eg,
disseminatedintravascularcoagulation[DIC]inthesettingoftraumaorinfection)thismayalsorequire
investigation.(See'Otherlimitedlaboratorytesting'below.)
OtherlimitedlaboratorytestingNoadditionallaboratorytestingisabsolutelyrequiredbeyond
coagulationtestingoutlinedabove.(See'Assessmentofanticoagulationstatus'above.)
However,dependingontheseverityofbleeding,weoftenperformacompletebloodcount(CBC)toassess
theserumhemoglobinlevelandplateletcountbecausetransfusionsofredbloodcellsandplateletsmaybe
indicatedinsomepatients.
Itmayalsobeappropriateinsomepatients(eg,trauma,incompletehistory)toevaluateforothercausesof
prolongedcoagulationtimes,includingliverdisease,nutritionaldepletionofvitaminK,disseminated
intravascularcoagulation(DIC),ortheuseofanonDOACanticoagulant.Assessmentofabnormalrenalor
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hepaticfunctionisimportantbecausetheseconditionscouldaffectbleedingdirectly(bycausingimpaired
plateletfunctionorcoagulopathy,respectively)orindirectly(byreducingmetabolismoftheanticoagulant).
HemoglobinlevelThehemoglobinlevelishelpfulincasesofmajorbleeding(eg,gastrointestinal),
bothtoassesstheseverityofbleedingandtodeterminewhetherredbloodcelltransfusionisindicated.
Patientswithactivebleedingcannotbemanagedexclusivelybyserialhemoglobinlevels,becausethe
rateofbleedingmayoutpacevolumeredistributionand/ortheabilitytoaccuratelymeasurechangesin
bloodloss.(See"Useofbloodproductsinthecriticallyill",sectionon'Redbloodcells'and"Approachto
acuteuppergastrointestinalbleedinginadults",sectionon'Bloodtransfusions'and"Initialevaluationand
managementofshockinadulttrauma",sectionon'Transfusionofredbloodcells'.)
Hemoglobinthresholdsfortransfusioninhemodynamicallystablepatientsarediscussedseparately.(See
"Indicationsandhemoglobinthresholdsforredbloodcelltransfusionintheadult".)
PlateletcountWeusuallymeasuretheplateletcounttoeliminatethepossibilityofthrombocytopenia
contributingtobleeding.Platelettransfusionsareindicatedforthetreatmentofmajorbleedinginpatients
withthrombocytopeniaregardlessoftheunderlyingcause.Specificthresholdsforplatelettransfusion
dependontheseverityofthebleeding.(See"Clinicalandlaboratoryaspectsofplatelettransfusion
therapy",sectionon'Indicationsforplatelettransfusion'.)
Theevaluationofunexpectedthrombocytopeniaisdiscussedseparately.(See"Approachtotheadult
withunexplainedthrombocytopenia".)
Theplateletcountisnormalinpatientsreceivingaspirinandotherantiplateletagents,butplatelet
transfusionmaybehelpfulifbleedingisespeciallysevere.
RenalfunctiontestsGiventherenaldependenceofDOACs,determinationofcreatinineand
calculationofthecreatinineclearanceshouldbeperformedinallpatientswithsignificant,unexplained
bleeding.Uremiamayalsoimpairplateletfunction,furtherreducinghemostasis.(See"Platelet
dysfunctioninuremia".)
LiverfunctiontestsWeassessliversyntheticfunctioninpatientswithprolongedPTorothersignsor
symptomssuggestiveofliverdisease,toassessthepossibilitiesofreducedclearanceofdirectfactorXa
inhibitors,whicharepartiallymetabolizedintheliver.Diminishedhepaticfunctionmayalsocontributeto
bleedingifcoagulationfactorsynthesisisimpaired.Theseissuesarediscussedseparately.(See"Clinical
useofcoagulationtests",sectionon'Evaluationofabnormalresults'.)
DICtestsPatientswithsuspecteddisseminatedintravascularcoagulation(DIC)inthesettingoftrauma
orsepsismayhaveadditionalmeasurementssuchasfibrinogenandDdimertesting.Thissubjectis
discussedindetailseparately.(See"Clinicalfeatures,diagnosis,andtreatmentofdisseminated
intravascularcoagulationinadults",sectionon'Diagnosticevaluation'.)
MAJORBLEEDING
OverviewofmanagementPatientswithserious/majorbleedingshouldbemanagedinanintensivecare
settingwithappropriatehemodynamicsupport.Optionsforthemanagementofbleedingincludeobservation
drugremovalwithactivatedcharcoaland/orhemodialysisandactiveinterventionsincludingadministrationof
antifibrinolyticagents,potentiallyprothromboticclottingfactorproducts,and/orsurgery[29].Theappropriate
approachfromamongtheseoptionsdependsonongoingassessmentoftheseverityofbleeding(table2).
Additionalaspectsofmanagementforallpatientswithmajorbleedingincludethefollowing:
Immediatediscontinuationofallanticoagulantandantiplatelettherapymustbeclearlydescribedinthe
medicalrecordandorderingsystem.Thisincludesdiscontinuationoftheanticoagulantthepatientis
taking,andavoidanceofotheranticoagulants(eg,"routine"ordersforheparinadministrationforvenous
thromboembolismprophylaxis).
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Rapidandcontinuoushemodynamicassessment.
Establishmentofaneffectiveairwayandlargeboreintravenousaccess.
Optimizationofbodytemperature,bloodpH,andelectrolytebalance,includingcalcium.
Transfusionsifrequired,includingredbloodcellsforsevereanemiaorongoingbloodlossplateletsfor
thrombocytopeniaand/orsevereplateletdysfunctionandplasmafortraumaassociatedcoagulopathy.
(See'Transfusionsifneeded'below.)
Earlyinvolvementofappropriatespecialistsisvitalfordefinitiveinterventionsatthesite(s)ofbleeding,which
canbebothdiagnosticandtherapeutic.Theconsultingendoscopistorsurgeonshouldbenotifiedimmediately
regardingthepotentialneedforinterventioninapatientwithbleedingthatis(ormaybecome)severe.
Intracerebralhemorrhage(ICH)ICHisofgreatconcernbecausebleedingincreasesintracranial
pressure,andexpansionofthehematomaiscommon.Importantly,thediagnosisofICHisconfirmedby
noncontrastcomputedtomographyormagneticresonanceimaging,whicheverisfastesthowever,
empirictreatmentforsuspectedICHintheabsenceofintracranialimagingmaybeappropriateinsome
cases(eg,whenthetimedelayinobtainingintracranialimagingcouldbelifethreatening).
AdditionalconsiderationsinthemanagementofICHandsubduralhemorrhagearediscussedindetail
separately.(See"Spontaneousintracerebralhemorrhage:Treatmentandprognosis"and"Subdural
hematomainadults:Prognosisandmanagement".)
OtherbleedingsitesOthermajorbleedingsitesmayincluderetroperitonealbleeding,compartment
syndrome,andmassivegastrointestinalbleeding.AdditionalconsiderationsinthemanagementofICH
thesetypesofmajorbleedingarediscussedindetailseparately.(See"Approachtoacuteupper
gastrointestinalbleedinginadults"and"Approachtoacutelowergastrointestinalbleedinginadults"and
"Approachtoabnormaluterinebleedinginnonpregnantreproductiveagewomen"and"Initial
managementoftraumainadults"and"Abdominalcompartmentsyndromeinadults"and"Acute
compartmentsyndromeoftheextremities".)
Anticoagulantreversal
OverviewofreversalstrategyReversalofanticoagulationisgenerallythoughttobedesirableina
patientwithseriousorlifethreateningbleedingwhoremainsactivelyanticoagulated,althoughrandomized
trialdatatosupportthispracticearelacking.Areversalagentisavailablefordabigatranbutnotfortheoral
directfactorXainhibitors.OtheravailablestrategiesforreversingtheanticoagulanteffectofDOACagents
includethefollowing(table2):
Drugremovalfromthecirculationand/orgastrointestinaltract
ProhemostatictherapiessuchasantifibrinolyticagentsandDDAVP
Prothrombincomplexconcentrates(PCCs),whichmaybeprothrombotic
Highqualityevidencefromrandomizedtrialsislackingforthesestrategiesthus,ourpracticeisbasedon
clinicalexperienceanddatafromcaseseries[29,30].
InmostcasesofmajorDOACassociatedbleeding,wesuggesttheuseofanantifibrinolyticagentandthe
removalofexcessdrugusinghemodialysis(fordabigatran)and/ororalactivatedcharcoal(forallagents),
especiallyifthelastanticoagulantdosewastakeninthepreviousfewhours.(See'Dabigatranreversal'below
and'Rivaroxaban,apixaban,edoxaban(reversal)'below.)
Wereservemorepotenttherapies,suchasidarucizumab(fordabigatran)andactivatedorunactivated
prothrombincomplexconcentrates(aPCCsorPCCs,respectively)(table4),forthemostserious/life
threateningcasesofDOACassociatedbleedingsuchasongoingbleedingthatislikelytoleadtodeathor
permanentdisabilityifnotstoppedimmediately.However,PCCshavethepotentialtocausethrombosisat
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dosesusedtotreatbleeding,andtheirefficacyintreatingDOACassociatedbleedinghasnotbeenvalidated
inprospectiveclinicaltrials.Availabledataconsistlargelyofnonbleedingvolunteers,casereports,and
preclinicalmodels[3140].Thus,weavoidPCCsinpatientswithlessseverebleeding.Importantly,useof
theseproductsshouldnotbeconsideredroutineor"standardofcare."(See'Clottingfactorproducts'below.)
WegenerallyavoidtheuseofrecombinantactivatedfactorVII(rFVIIa),FreshFrozenPlasma(FFP),or
cryoprecipitateinDOACassociatedbleedingbecausetherearenodatatosupporttheuseoftheseproducts,
andthereareassociatedrisks(eg,thrombosis,volumeoverload,transfusionreactions).Anexceptionisthe
useofFFPtocorrectacoexistingcoagulopathy(eg,fromtrauma).(See'Transfusionsifneeded'below.)
Asdiscussedabove,abnormalcoagulationtestingisconsistentwiththepresenceofcontinuedDOACeffect,
butnormaltestingdoesnotnecessarilyeliminatethepossibilityofclinicallyimportantconcentrationsofthese
agents.Therefore,theresultsofcoagulationtests,ortheirtrendsovertime,donotmeaningfullyinform
reversalofDOACassociatedbleeding.Managementisbasedonthepatient'spresentationandchangein
theirstatusovertimeratherthanontheresultsofcoagulationtestinginmostcases.(See'Assessmentof
anticoagulationstatus'above.)
DabigatranreversalIdarucizumab(Praxbind)canbeusedforemergencyreversaloftheanticoagulant
effectofdabigatran[41,42].Wewouldadministerthisagent,ifavailable,forpatientsforwhommore
conservativebleedingmanagementmeasureshavebeenineffectiveandwhohavetrulylifethreatening
bleedingorwhorequiretrulyemergentsurgery.Wewouldonlyadministerthedrugtopatientswithconvincing
evidenceofsignificantdabigatranlevelsbasedonclinicalhistoryofingestionorlaboratorytesting.
Theuseofidarucizumabinreversingdabigatrananticoagulationwasdemonstratedinaninterimreportofthe
REVERSEADstudy(ReversalEffectsofIdarucizumabonActiveDabigatran).Thisreportincluded90
patientswithseriousbleedingortheneedforanurgentinvasiveprocedure(<8hours)whilereceiving
dabigatranwhoallreceivedidarucizumab[43]:
Patientsweremostlyelderlywithatrialfibrillation(medialage76.5years),andbleedingsitesincluded
intracranial(approximatelyonethirdofpatients),gastrointestinal,traumatic,andsurgical.
Twodosesof2.5gramsofidarucizumabweregiven15minutesapart.
Reversalwasassessedusingadilutethrombintime(TT)andecarinclottingtime(ECT)measuredata
centrallaboratory.Bythismeasure,idarucizumabcompletelyreversedanticoagulationinover90percent
ofpatientswithinthefirst10to30minutesofinfusion.
Themediantimetocessationofbleeding(asecondaryendpoint)was11.4hours,althoughthisfigure
principallyreflectsthetimeatwhichbleedingcessationwasassessed,notthetruetimethatbleeding
stopped.Inpatientsrequiringanurgentsurgicalprocedure,"normalhemostasis"asjudgedbythe
operatingsurgeonwasachievedin33of36surgicalpatients(92percent).Therewerefivethrombotic
eventsand18deathswithoutacontrolgroupitisunclearhowanyoftheseeventrateswouldcompare
withoutcomesinsimilarpatientswhodidnotreceiveidarucizumab[44].
Inhealthyvolunteers,idarucizumabcausedonlymildadverseevents(eg,infusionsiteerythema),andit
effectivelyneutralizeddabigatraninadosedependentmannerbyavarietyofclottingassays[45].Inarat
model,idarucizumabneutralizeddabigatranactivityatnanomolarconcentrationsanddidnotmimicthrombin
functionally(ie,itdidnotbindtothrombinsubstrates,alterclottingparameters,orcauseplateletaggregation
onitsown)thus,itisnotexpectedtohaveanyanticoagulanteffect[46].
Idarucizumabconsistsofhumanizeddabigatranspecific(Fab)antibodyfragmentsassuch,itdoesnothave
anyknownactivityagainstdirectfactorXainhibitorsorotheranticoagulants[46].
ImminentriskofdeathForpatientswhoareatimminentriskofdeathfrombleedingassociatedwith
dabigatrananticoagulation,wesuggestadministrationofidarucizumab,ifavailable,intwo2.5gram
doses(total=5mg)intravenously,nomorethan15minutesapart[42].Wewouldnotcombine
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idarucizumabwith"procoagulant"reversalagentssuchasactivatedprothrombincomplexconcentrate
(aPCC).Ifidarucizumabisnotavailable,wesuggestadministeringanaPCCsuchasfactoreightinhibitor
bypassingactivity(FEIBA),atadoseof50to80units/kg.IfanaPCCisunavailable,anunactivated4
factoror3factorPCCwouldbeareasonablealternativeatadoseof50units/kg(table4).
Supplementationof3factorPCCwithFreshFrozenPlasmahasbeenusedtosupplyfactorVII,whichis
presentatminimallevelsin3factorPCCs.Importantly,treatmentwithaPCCscarriesarealand
substantialprothromboticrisk,andtheseagentshavenotbeenstudiedadequatelyinpatientsreceiving
dabigatran,soweavoidtheiruseexceptinextremeclinicalcircumstances.
Wealsousethestrategieslistedbelowforlessseverebleeding,includinganantifibrinolyticagent,oral
activatedcharcoaland/orhemodialysiswhenappropriate,anddrugdiscontinuation.
Thepracticeoftreatingimmediatelylifethreateningbleedingfromdabigatranwithidarucizumabisbased
onthestudyinpatientswithdabigatranassociatedbleedingdescribedabove[43].TheuseofanaPCC
inthissettingisbasedonlowqualityevidencesuggestingthataPCCsorunactivatedPCCsmay
attenuatebleedingorcorrectcoagulationtestsinexperimentalmodelsofbleeding[3140].However,
aPCCsshouldnotbeconsideredstandardofcareforthemanagementofdabigatranassociated
bleeding,becauseevidenceforimprovedclinicaloutcomesislackingandtheseprohemostaticproducts
arelikelytoincreasetheriskofthrombosis.Therefore,clinicaljudgmentisrequiredindeterminingthe
individualbleedingandthromboticrisksofeachpatientonacasebycasebasis.Formostpatientswith
bleeding,wesuggestnotusingidarucizumaboranaPCC,basedonthelackofsupportingdataand/or
thepotentialprothromboticrisks.(See'Clottingfactorproducts'below.)
MajorbleedingForpatientswithmajor(includinglifethreatening)bleeding,wesuggestadministration
ofanantifibrinolyticagent(eg,tranexamicacid,aminocaproicacid).Theuseoftheseagentsmayalso
beappropriateinindividualswithlessseriousbleedingifthepatienthasongoingbleedingorother
comorbiditiesthatincreasebleedingrisk.(See'Antifibrinolyticsandotherprohemostatictherapies'
below.)
Wealsosuggesttheadministrationoforalactivatedcharcoaltoremovetheunabsorbedprodrug
(dabigatranetexilate)fromthegastrointestinaltractifthelastdosewaswithintheprevioustwohoursand
thepatientcantoleratetheoralcharcoaladministration(ie,notvomiting,adequatementalstatus).Oral
activatedcharcoalmayalsobeusefulforindividualswithlessseverebleedingwhomayhavetakenan
overdoseofdabigatranwhosebleedingisongoingorwhohaveotherhemostaticdefectsthatcould
increasetheriskofmoreseverebleeding.
Hemodialysismayalsobeusedtoremoveactivedabigatranfromthecirculation[47,48].Studiesin
patientswithrenalimpairmenthaveshownremovalofapproximatelyhalfofthecirculatingdrugby
hemodialysis,withaminorredistributionaftercompletionofthedialysis[4952].
Asnotedabove,discontinuationofdabigatranshouldbeclearlydescribedinthemedicalrecordand
orderingsystem,andotheranticoagulantsshouldbeavoided.(See'Overviewofmanagement'above.)
MinorbleedingMinorbleedingcanusuallybemanagedconservatively.(See'Minorbleeding'below.)
Rivaroxaban,apixaban,edoxaban(reversal)ThereisnospecificantidoteforthedirectfactorXa
inhibitors(eg,rivaroxaban,apixaban,edoxaban).Thefollowingmaybehelpful,althoughevidencefrom
randomizedtrialsislackingregardingthesestrategies:
ImminentriskofdeathForpatientswhoareatimminentriskofdeathfrombleedingassociatedwith
directfactorXainhibitoranticoagulation,wesuggestadministeringanunactivated4factorPCC(table4)
atadoseof50units/kg.Ifa4factorPCCisunavailable,a3factorPCCcanbeusedsupplementationof
3factorPCCwithFreshFrozenPlasmahasbeenusedtosupplyfactorVII,whichispresentatminimal
levelsin3factorPCCs.Importantly,treatmentwithPCCscarriesarealandsubstantialprothrombotic
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risk,andtheseagentshavenotbeenstudiedadequatelyinpatientsreceivingfactorXainhibitors,sowe
avoidtheiruseexceptinextremeclinicalcircumstances.
ThispracticeoftreatingimmediatelylifethreateningbleedingfromafactorXainhibitorwithan
unactivatedPCCisbasedontheabilityofPCCstoattenuatebleedingorcorrectcoagulationtestsin
experimentalmodelsofbleeding[3140,53].However,PCCsshouldnotbeconsideredstandardofcare
inthissetting,becausethereisnoclinicalevidencetosupporttheiruseinpatientswithDOACassociated
bleeding,andtheseprohemostaticproductsarelikelytoincreasetheriskofthrombosis.Therefore,
clinicaljudgmentisrequiredindeterminingtheindividualbleedingandthromboticrisksofeachpatienton
acasebycasebasis.Formostpatientswithbleeding,wesuggestnotusingaPCC,basedonthelackof
supportingdataandtheprothromboticrisks.(See'Clottingfactorproducts'below.)
Wealsousethestrategieslistedbelowforlessseverebleeding,includinganantifibrinolyticagent,oral
activatedcharcoalwhenappropriate,anddrugdiscontinuation.
MajorbleedingForpatientswithmajorbleeding(includinglifethreateningbleeding),wesuggest
administrationofanantifibrinolyticagent(eg,tranexamicacid,aminocaproicacid).Theuseofthese
agentsmayalsobeappropriateinindividualswithlessseriousbleedingifthepatienthasongoing
bleedingorothercomorbiditiesthatincreasebleedingrisk.(See'Antifibrinolyticsandotherpro
hemostatictherapies'below.)
Forpatientswithmajorbleeding(includinglifethreateningbleeding),wesuggestadministrationoforal
activatedcharcoaltoremoveunabsorbeddrugfromthegastrointestinaltractifthelastdoseofthe
anticoagulantwasrecentenoughthatunabsorbeddrugislikelytobepresent(rivaroxaban:withineight
hoursapixaban:withinsixhoursedoxaban:withintwohours)[5456].
TheavailableoraldirectfactorXainhibitorscannotbedialyzed,becausetheyarehighlyproteinbound
[57].Charcoalhemofiltrationhasbeensuggestedbutnottoourknowledgeevaluatedorusedinpatients
withbleedingcomplications.
Asnotedabove,discontinuationofthefactorXainhibitorshouldbeclearlydescribedinthemedical
recordandorderingsystem,andotheranticoagulantsshouldbeavoided.(See'Overviewof
management'above.)
MinorbleedingMinorbleedingcanusuallybemanagedconservatively.(See'Minorbleeding'below.)
ClottingfactorproductsSeveralproductsconsistingofcoagulationfactorsintheunactivatedor
activatedstateareavailable.Theseproductshavebeendevelopedfortreatingbleedinginothersettingsdata
arelackingregardingtheefficacyofanyoftheseproductsinpatientswithDOACassociatedbleeding.
Unactivatedprothrombincomplexconcentrates(PCCs)Unactivatedprothrombincomplex
concentrates(PCCs)areconcentratesofcoagulationfactorsandanticoagulantspurifiedfromplasma.
Theycontainhighlevelsofthreeorfourcoagulationfactors(II,IX,andXin3factorPCCsII,VII,IX,and
Xin4factorPCCs),alongwithproteinCandS(table4).Additionaldetailsregardingtheseproductsare
presentedseparately.(See"Reversalofanticoagulationinwarfarinassociatedintracerebral
hemorrhage",sectionon'Unactivatedprothrombincomplexconcentrates'.)
PCCsarebeststudiedforreversingwarfarinanticoagulationdataregardingtheirefficacyinDOAC
associatedbleedingarelimitedtohealthyvolunteersandanimalmodels.Asexamples:
A4factorPCCcorrectedrivaroxabaninducedimpairedthrombingenerationin10nonbleeding
volunteers,inadosedependentmanner[31].
In12nonbleedingvolunteers,a4factorPCCwasabletoreverserivaroxabanassociated
prolongationinthePTandtonormalizetheendogenousthrombinpotential[58].
Inarabbithemorrhagicmodel,a4factorPCCdidnotreverserivaroxabaninducedbleeding[59].
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Theextenttowhichthispreclinicalevidencecorrelateswithinvivoefficacyforthemanagementof
bleedinginhumansisnotknown[60].
WhenweusePCCs,westartatadoseof50to80units/kg.UnitsrefertointernationalunitsoffactorIX
activity.Ifthetherapyappearsineffective,wetypicallywouldnotreadministertheproduct,becauseitis
unlikelythattheriskbenefitratioofdoingsowouldbefavorable.IfhemostasisisimprovedafterPCC
administration,wealsowouldnotreadministerthemedicationunlessapatient'srenalfunctionis
impairedandtheexpectedclearanceoftheDOACwillbesignificantlydelayed.Insuchcases,arepeat
doseofthePCCmaybeappropriate12to24hoursafterthefirstdose.
ActivatedPCCs(aPCCsfactorVIIIinhibitoractivitybypassingagent[FEIBA])ActivatedPCCs
(aPCCs)arePCCsthatcontainatleastonefactorintheactivatedformtheseproductshavebeen
developedandusedforpatientswithhemophiliawhohavebleedinginthesettingofafactorinhibitor.
FEIBAistheonlyaPCCavailableintheUnitedStatesotheraPCCsareavailableelsewhere.InFEIBA,
factorVIIismostlyactivated.
WhenweuseFEIBA,westartatadoseof50units/kg.Ifthetherapyappearsineffective,wetypically
wouldnotreadministertheproduct,becauseitisunlikelythattheriskbenefitratioofdoingsowouldbe
favorable.IfhemostasisisimprovedafteraPCCadministration,wealsowouldnotreadministerthe
medicationunlessapatient'srenalfunctionisimpairedandtheexpectedclearanceoftheDOACwillbe
significantlydelayed.Insuchcases,arepeatdoseofFEIBAmaybeappropriate12hoursafterthefirst
dosethetotaldailydoseshouldnotexceed200units/kg.
TherearenohighqualitydatafrompatientswithDOACassociatedbleedingtosupporttheuseofanyof
theseproductshowever,theirusehasbeendescribedincasereports,smallseries,andpreclinical
researchsettings.Asexamples:
Inaseriesof127patientswithaDOACassociatedintracerebralhemorrhage(ICH)whowere
treatedwithFEIBAat50units/kg,noneofthepatientshadexpansionoftheICH,andtherewereno
thromboticorhemorrhagiccomplications[61].
Inastudyin10nonbleedingindividuals,FEIBAcorrectedrivaroxabaninducedimpairedthrombin
generationinadosedependentmanner[31].
Inapigpolytraumamodel,aPCCatadoseof50mg/kgpreventedfatalbleedingwhencompared
withplaceboorlowerdoseaPCC[62].
Inbaboonstreatedwithrivaroxaban,FEIBAatadoseof50to100units/kgwasreportedtocorrect
thebleedingtime[63].
Theextenttowhichthepreclinicalevidencecorrelateswithinvivoefficacyforthemanagementof
patientswithDOACassociatedbleedingisnotknown.
RecombinantactivatedfactorVII(rFVIIa)Wegenerallyavoidtheuseofrecombinantactivated
factorVII(rFVIIa)totreatDOACassociatedbleeding.AlthoughrFVIIaappearstorestoresomeinvitro
measuresofcoagulation,animalbleedingmodelsdonotsuggestthatrFVIIawouldbebeneficialforthe
treatmentofdabigatranorrivaroxabanassociatedbleeding.
FreshFrozenPlasmaWedonotuseplasmaproductssuchasFreshFrozenPlasma(FFP)or
PlasmaFrozenWithin24HoursAfterPhlebotomy(PF24)toreversetheanticoagulanteffectofDOACs.
Thispracticeisbasedonlackofanyevidencethattheseproductsimproveclinicaloutcomes,alongwith
severalpotentialrisksincludingvolumeoverload,transmissionofinfection,andtransfusionreactions.
(See"Clinicaluseofplasmacomponents",sectionon'Risks'.)
However,plasmaproductsmaybeappropriateaspartofamassivetransfusionprotocolinpatientswith
severebleedingwhohavedevelopedadilutionalcoagulopathy.(See'Transfusionsifneeded'belowand
"Massivebloodtransfusion".)
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Severalmechanismsmaycontributetothepotentialefficacyoftheseproductsnonehavebeendefinitively
demonstratedtoworkbythesemechanismsinthesettingofDOACassociatedbleeding.Clottingfactors
circulateinanunactivatedformandbecomeactivatedatthesiteofawound.Thus,administrationofthe
unactivatedproductsmightbeeffectiveprimarilyby"overwhelming"theanticoagulantratherthanby
promotinghemostasis.Incontrast,theactivatedproductsmaypromotehemostasisdirectlybyproviding
activatedfactorsatsitesofbleeding.
AntifibrinolyticsandotherprohemostatictherapiesOthertherapiestoenhancehemostasisina
bleedingpatientincludethefollowing:
Antifibrinolyticagentsincludingtranexamicacidandaminocaproicacidcanbeusedforsevere
bleeding.Bothcanbeadministeredorallyorintravenouslyintravenousadministrationisgenerally
favoredforthosewithmajororlifethreateningbleeding.
Theusualoraldoseoftranexamicacidis1to1.5gramsevery8to12hoursforthedurationof
bleeding.Intravenousdosesarelesswellcharacterizeddosesof10to20mgperkgasan
intravenousbolusfollowedby10mgperkgintravenouslyeverysixtoeighthourshavebeenusedin
patientswithmajorbleeding,hemophilicbleeding,oraftermajortrauma.Aftercardiacsurgery,
dosesof10to15mgperkgasanintravenousbolusfollowedby1mgperkgperhourfor6to10
hourshavebeenused.Tranexamicacidexcretionishighlydependentonrenalfunctiontheinterval
betweendosesissubstantivelyincreasedinpatientswithrenalinsufficiency.
Thedoseofaminocaproicaciddependsontheurgencywithwhichthebleedingneedstobe
reversed.Atypicalstartingdoseis2gramsintravenouslyeverysixhoursasmuchas1gram
intravenouslyeveryhourcanbegiven.aminocaproicacidcanalsobeadministeredorallyatadose
of3gramsthreetofourtimesperday.
Desmopressin(DDAVP)canbeusedforimpairedplateletfunctionsuchasoccursinthesettingofuremia
orantiplateletagents.Typicaldosingis0.3mcg/kggivensubcutaneouslyorintravenously(in50mLof
normalsalineover15to30minutesifgivenintravenously),whichmayimproveplateletfunctionfor
severalhours.Weusuallydonotgivemorethantwodosesbecausetachyphylaxisoftendevelopsafter
theseconddose,andrepeatedadministrationofdesmopressincanbecomplicatedbyhyponatremia.
HighqualitydataarelackingregardingtheefficacyoftheseagentsinthesettingofDOACrelatedbleeding.
However,giventheirlowriskofthrombosis,lowcost,andwidespreadavailability,theseagentsmaybe
appropriateinpatientswithmajororlifethreateningDOACassociatedbleeding.
Additionaldetailsregardingtheantifibrinolyticagentsarepresentedseparately.(See"Thromboticand
hemorrhagicdisordersduetoabnormalfibrinolysis",sectionon'Tranexamicacidandepsilonaminocaproic
acid'.)
TransfusionsifneededTransfusionsareacomponentofsupportivecareforseverebleeding.(See
"Initialevaluationandmanagementofshockinadulttrauma",sectionon'Transfusionforsevereongoing
hemorrhage'.)
Redbloodcells(RBCs)RBCtransfusionmayberequired,dependingontherateofbleedingand
amountofbloodloss.(See"Initialevaluationandmanagementofshockinadulttrauma",sectionon
'Transfusionofredbloodcells'and"Indicationsandhemoglobinthresholdsforredbloodcelltransfusion
intheadult".)
PlateletsPlatelettransfusionisnotusedtoreversetheanticoagulanteffectofDOACsinapatientwith
anormalplateletcounthowever,thrombocytopenicpatientswithbleedingshouldbetreatedforthe
underlyingcauseofthrombocytopeniaandreceiveplatelettransfusionsifthethrombocytopeniaissevere
andbleedingismajororlifethreatening.Platelettransfusionsmayalsobeusedinpatientswithsevere
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bleedinginthesettingofantiplateletmedicationssuchasaspirin.(See"Clinicalandlaboratoryaspectsof
platelettransfusiontherapy".)
FreshFrozenPlasma(FFP)FFPmaybegivenaspartofamassivetransfusionprotocol,toreplace
coagulationfactorslostbybleedingandreplacementofpackedRBCs,whichdonotcontaincoagulation
factorsatreplacementlevels.Incontrast,thereisnoevidencetosupporttheuseofFFPasareversal
strategyinDOACassociatedbleeding.(See'Clottingfactorproducts'aboveand"Massiveblood
transfusion"and"Useofbloodproductsinthecriticallyill".)
MINORBLEEDINGMinorbleeding(eg,epistaxis,bruising,slowgastrointestinalbleeding)canusuallybe
managedconservativelyusinglocalhemostaticmeasures(eg,mechanicalpressure).Decisionstotemporarily
discontinuetheanticoagulantmustbalancebleedingandthromboticrisksforeachpatientonacasebycase
basis(table2).
Theuseofantifibrinolyticagentsmayoccasionallybeappropriateinindividualswithlessseriousbleedingif
thepatienthasongoingbleedingorothercomorbiditiesthatincreasebleedingriskhowever,theseagents
generallyarenotrequiredforminorbleeding.Wedonotadministerprothrombincomplexconcentrates
(PCCs)forminorbleeding.
SURGERY/INVASIVEPROCEDUREGiventheshorthalflivesoftheDOACs,itisoftenpossibletodelaya
procedurelongenoughtoallowmostoralloftheanticoagulanteffecttodissipatespontaneouslyinpatients
withnormalrenalfunction.However,ifurgentoremergentsurgeryisrequiredandthereisinsufficienttimeto
allowtheanticoagulanteffecttodissipate,reversalstrategiesdiscussedhereinmaybeappropriate.Decisions
regardingtheneedforreversalareindividualizedbasedontheurgencyandbleedingriskoftheprocedure.
PerioperativemanagementofDOACsinthesettingofelectivesurgeryisdiscussedseparately.(See
"Perioperativemanagementofpatientsreceivinganticoagulants".)
RESUMPTIONOFANTICOAGULATIONDecisionstoresumeanticoagulationfollowingableedingevent
areindividualizedbasedontherisksandbenefitsforeachpatient.Detailsarepresentedinindividualtopic
reviewsonspecifictypesofbleedingandunderlyingindicationsforanticoagulation:
Intracerebralhemorrhage(See"Theuseofantithrombotictherapyinpatientswithanacuteorprior
intracerebralhemorrhage".)
Gastrointestinalbleeding(See"Managementofanticoagulantsinpatientsundergoingendoscopic
procedures"and"Overviewofthetreatmentofbleedingpepticulcers",sectionon'Riskfactorsfor
persistentorrecurrentbleeding'.)
Atrialfibrillation(See"Atrialfibrillation:Anticoagulanttherapytopreventembolization".)
Venousthromboembolism(See"Rationaleandindicationsforindefiniteanticoagulationinpatients
withvenousthromboembolism"and"Venousthromboembolism:Initiationofanticoagulation(first10
days)".)
ANTIDOTESUNDERDEVELOPMENTThefollowingstrategiesareatvariousstagesofdevelopment:
FactorXainhibitorantidoteAndexanetalfa(PRT064445)isareversalagentforallfactorXa
inhibitors,includingthedirectfactorXainhibitorsaswellaslowmolecularweight(LMW)heparinsand
fondaparinux,whichinhibitfactorXaindirectly[64].ItisacatalyticallyinactiveformoffactorXaproduced
recombinantly.Itactsasa"decoy"proteinthatbindsandsequesterstheanticoagulant.Byitself,
andexanetdoesnotappeartoaffectcoagulation.
InapreliminaryreportfromtheANNEXA4study,outcomeswithandexanetforthetreatmentofserious
bleedingwereevaluatedin47patients(meanage,77years)whowerereceivingafactorXainhibitorfor
atrialfibrillationorvenousthromboembolism(VTE)andhadhighantifactorXaactivity[65].Mostofthe
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patientswerereceivingrivaroxabanorapixabanforatrialfibrillationonlyonewasreceivingLMW
heparin.
Hemostasiswasjudgedtobeexcellentin31ofthe47(66percent)andgoodinsix,andantifactor
Xaactivitywasreduceddramaticallyforseveralhours.
Adverseeventsincludedthrombosesin12of67patients(18percent),whichincludedthe47with
highantifactorXaactivityplusanadditional20whoreceivedthedrugbutlaterwereassessednotto
havehighantifactorXaactivity.ThethrombosesincludedfivestrokesandeightVTEs.These
occurredfrom3to30daysafterandexanetwasadministered,andonlyonepatientwhohada
thrombosiswasreceivingtherapeuticdoseanticoagulationatthetimeoftheevent.Apriorstudyin
101healthyvolunteersages50to75didnotobserveanythrombosesorothermajoradverseeffects
[66].
Dosingofandexanetusesabolusfollowedbyatwohourinfusion.IntheANNEXA4study,patientswho
hadtakenapixabanorrivaroxabanmorethansevenhourspriorreceivedabolusof400mgandan
infusionof480mg(4mg/minutefortwohours)[65].Forpatientswhohadtakenenoxaparin,edoxaban,
orrivaroxabanwithintheprevioussevenhoursoratanunknowntime,theboluswas800mgandthe
infusion960mg(8mg/minfortwohours).Andexanetisnotyetavailableforclinicalorcompassionate
usetheANNEXA4trialisongoing.
UniversalDOACantidotes
Asmallmoleculeantidote(PER977Ciraparantag)hasbeenshowninpreliminarystudiestobind
directlyandspecificallytodirectthrombininhibitors,factorXainhibitors,andheparins(including
LMWheparin),andtoreversetheiranticoagulantproperties[67].Oftheanticoagulants,edoxaban
requiredthelowestdoseforfullreversalofeffect.Inastudyof80healthyvolunteersgivenasingle
therapeuticdoseofedoxaban,PER977normalizedthewholebloodclottingtimewithin10minutes
incontrast,normalizationoftheclottingtimetook12to15hoursinindividualsgivenedoxaban
followedbyplacebo[68].Therewerenomajoradverseeffects.
FXaI16LisamutantformoffactorXathatintroducesanaminoacidsubstitution(isoleucinefor
leucine)atposition16thisagentisalsobeingexploredasapossibleuniversalbypassingagentfor
multipleanticoagulants[69].Ratherthanbindingtoananticoagulant,FXaI16Lcirculatesina
zymogenlike(inactive)state,isresistanttoactivesiteinhibitors,andbecomesactivatedwhenit
encountersactivatedfactorV(factorVa)ondamagedcellularsurfaces,restoringhemostasis
selectivelyatthesiteofbleeding.Inamousemodel,FXaI16Lwasabletoimproveclottingandreduce
bloodlossfollowingrivaroxabantreatmentitcouldalsoreversetheeffectofrivaroxabanor
dabigatraninvitroinhumanplasma[69].
SUMMARYANDRECOMMENDATIONS
Directoralanticoagulants(DOACs)reversiblyinhibitcoagulationfactorsandhaveashorterhalflifethan
warfarin.Availableagentsincludethedirectthrombininhibitordabigatran(Pradaxa)andthedirectfactor
Xainhibitorsrivaroxaban(Xarelto),apixaban(Eliquis),andedoxaban(Lixiana,Savaysa).(See
'Terminologyandsitesofaction'above.)
TheriskofmajorbleedingwithDOACsislowandgenerallysimilartoorlowerthanotheranticoagulants,
butlifethreateninghemorrhageshaveoccurred.(See'BleedingrisksfromDOACs'above.)
Weassesstheseverityofbleedingandthedegreeofanticoagulationthroughthepatienthistoryand
physicalexamination.Thedegreeofanticoagulationdependsonthedoseandtheintervalsincethelast
doseinsomecasescoagulationtestingmaybehelpfulindeterminingresidualanticoagulanteffect,but
normalcoagulationtestingdoesnotnecessarilyeliminatetheneedforaggressiveinterventions.Other
15/26
2016.12.02.
limitedlaboratorytestingincludesacompletebloodcount(CBC)andtestsofrenalandhepaticfunction.
(See'Patientassessment'above.)
InmostcasesofDOACassociatedbleeding,includingmajorbleeding,wediscontinuethedrugtransfuse
bloodproductsifnecessaryaddressthehemorrhageanatomically(eg,surgery,endoscopy,local
measures)andadministerprohemostatictherapiessuchasantifibrinolyticagents(table2).(See
'Overviewofreversalstrategy'aboveand'Transfusionsifneeded'aboveand'Antifibrinolyticsandother
prohemostatictherapies'above.)
Agentspecificinterventionsmayincludethefollowing:
DabigatranForpatientswithmajorbleeding,includinglifethreateningbleeding(eg,intracranial,
severegastrointestinal),wesuggestanantifibrinolyticagent(eg,tranexamicacid,aminocaproic
acid)(Grade2C).Wemayalsouseanantifibrinolyticagentinselectedpatientswithmajorbleeding
thatisnotimmediatelylifethreatening(eg,suspectedoverdose,comorbidities,worseningbleeding
symptoms).Wealsosuggestadministrationoforalactivatedcharcoalifthelastanticoagulantdose
waswithintheprevioustwohours(Grade2C).Hemodialysismaybeusedinselectedpatientsifthe
potentialforsignificantdrugremovalishigh.(See'Dabigatranreversal'above.)
Forpatientsatanimminentriskofdeathfrombleeding,inadditiontotreatmentwithan
antifibrinolyticagentanddrugremovalwithoralcharcoaland/orhemodialysis,wesuggest
administeringidarucizumab(Grade2C).Forthoseforwhomidarucizumabisnotavailable,we
suggestusinganactivatedprothrombincomplexconcentrate(aPCCeg,factoreightinhibitor
bypassingagent[FEIBA](table4))(Grade2C).WewouldnotgiveidarucizumabandanaPCC
together.Importantly,experiencewithidarucizumabislimited,andtreatmentwithPCCscarriesareal
andsubstantialprothromboticrisk,soweavoidtheseagentsexceptinextremeclinical
circumstances.Forpatientswithlessseverebleeding,wesuggestnotusinganaPCCor
idarucizumab(Grade2C).
Rivaroxaban,apixaban,edoxabanForpatientswithmajorbleeding,includinglifethreatening
bleeding(eg,intracranial,gastrointestinal),wesuggestanantifibrinolyticagent(eg,tranexamicacid,
aminocaproicacid)(Grade2C).Wemayalsouseanantifibrinolyticagentinselectedpatientswith
majorbleedingthatisnotimmediatelylifethreatening,(eg,suspectedoverdose,comorbidities,
worseningbleedingsymptoms).Wealsosuggestadministrationoforalactivatedcharcoalifthelast
doseoftheanticoagulantwasrecentenough(rivaroxabanwithineighthoursapixabanwithinsix
hoursedoxabanwithintwohours)(Grade2C).ThedirectfactorXainhibitorscannotbedialyzed.
(See'Rivaroxaban,apixaban,edoxaban(reversal)'above.)
Forpatientsatimminentriskofdeathfrombleeding,inadditiontotreatmentwithanantifibrinolytic
agentanddrugremovalwithactivatedcharcoal,wesuggestadministeringanunactivated4factor
PCC(table4)(Grade2C).Importantly,treatmentwithPCCscarriesarealandsubstantial
prothromboticrisk,andtheseagentshavenotbeenstudiedadequatelyinpatientsreceivingfactor
Xainhibitors,soweavoidtheiruseexceptinextremeclinicalcircumstances.Forpatientswithless
severebleeding,wesuggestnotusingaPCC(Grade2C).
Minorbleedingcanusuallybemanagedconservativelyusinglocalhemostaticmeasures(ie,without
anticoagulantreversal).Decisionstotemporarilydiscontinuetheanticoagulantmustbalancebleeding
andthromboticrisksforeachpatientonacasebycasebasis.(See'Minorbleeding'above.)
AdditionalinformationregardingadministrationanddosingofDOACsandperioperativeDOAC
managementispresentedindetailseparatelyspecificindicationsfortheseagentsarepresentedin
separatetopicreviews.(See"Directoralanticoagulants:Dosingandadverseeffects"and"Perioperative
managementofpatientsreceivinganticoagulants"and"Atrialfibrillation:Anticoagulanttherapytoprevent
embolization"and"Overviewofthetreatmentoflowerextremitydeepveinthrombosis(DVT)"and
"Venousthromboembolism:Initiationofanticoagulation(first10days)".)
16/26
2016.12.02.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic94788Version35.0
20/26
2016.12.02.
GRAPHICS
Coagulationcascade:Anticoagulanteffects
LMWheparinsincludeenoxaparin,dalteparin,andtinzaparin.Unfractionated
heparinandLMWheparininihbitbothfactorXaandthrombintheeffectofLMW
heparinsonthrombinislessthanthatofunfractionatedheparin.Fondaparinuxis
asyntheticpentasaccharidebasedontheminimalantithrombinbindingregionof
heparinthatinhibitsfactorXa.LMWheparins,unfractionatedheparin,and
fondaparinuxinhibitclottingfactorsbybindingtoantithrombin.
OraldirectfactorXainhibitorsincludeapixaban,rivaroxaban,andedoxaban.
Parenteraldirectthrombininhibitorsincludeargatrobanandlepirudin.Oraldirect
thrombininhibitorsincludedabigatran.
CoagulationfactorsareshownasRomannumerals.Onlytheactivatedforms
(withthesuffix"a")areshownforsimplicity.Thrombinisalsoknownasfactor
IIa.
LMW:lowmolecularweight.
Graphic94856Version3.0
21/26
2016.12.02.
TrialsofwarfarinversusneweranticoagulantsinAF*
Baselinecharacteristics
Study
drugand
dose
Mean
CHADS 2
score
Percent
onaspirin
Primaryoutcome
Majorbleedingdefinition
RELY
Dabigatran
110mg
twiceper
day
150mg
twiceper
day
2.1
40
Allstrokeandsystemic
embolism
Reductioninhemoglobinofat
least2g/dL[20g/L]or
symptomaticbleedingin
criticalorgan
ROCKETAF
Rivaroxaban 3.5
20mgonce
perday
36
embolism
Majorandnonmajorclinically
relevantbleeding
ARISTOTLE
Apixaban
5mgtwice
perday
31
embolism
Overtbleedingplusfallin
hemoglobinofatleast2g/dL
[20g/L]ortransfusionof2
unitsofpackedredblood
cells,occurringatacritical
site,orresultingindeath
2.1
Outcomeeventrates(percent/yr)
(newagent/warfarin)
Primary
outcome
RELY
ROCKETAF
Major
bleeding
Death
Stroke
(all)
Stroke
(hemorrhagic)
Percent
timein
INRrange
110mg
1.53/1.69
(A)
2.71/3.36
(C)
3.75/4.13
1.44/1.57
0.12/0.38(C)
64
150mg
1.11/1.69
(B)
3.11/3.36
3.64/4.13
1.01/1.57
(C)
0.10/0.38(C)
64
Astreated
analysis
1.70/2.20
(A)
3.60/3.40
1.90/2.20
2.61/3.12
0.50/0.70(C)
55
Intentionto
treat
analysis
2.10/2.40
(A)
4.50/4.90
1.27/1.60
(B)
2.13/3.09
(B)
3.52/3.94
(B)
1.19/1.51
0.24/0.47(C)
62
ARISTOTLE
CHADS 2 :estimateofstrokerisk(A):statisticallysignificantfornoninferiority(B):statisticallysignificantfor
superiority(C):statisticallysignificant.
*TargetINR2.0to3.0ineachstudy.
Meanfollowupofapproximatelytwoyearsineachstudy.
Doseofrivaroxabanadjustedto15mgperdayforrenalinsufficiency(creatinineclearance30to49mL/minute[0.5to
0.82mL/second]).
Doseofapixabanadjustedto2.5mgtwiceperdaywithtwoormoreof:age80years,bodyweight60kg,orrenal
insufficiency(serumcreatininelevel1.5mg/dL[133mol/L]).
References:
1.ConnollySJ,EzekowitzMD,EikelbloomYS,etal.DabigatranversuswarfarininpatientswithatrialfibrillationN
EnglJMed2009361:1139.
2.PatelMR,MahaffeyKE,GargJ,etal.RivaroxabanversuswarfarininnonvalvularatrialfibrillationNEnglJMed
2011365:883.
3.GrangerCB,AlexanderJH,McMurrayJJV,etal.ApixabanversuswarfarininpatientswithatrialfibrillationNEngl
JMed2011365:981.
22/26
2016.12.02.
Directoralanticoagulantassociatedbleedingreversalstrategies
Typeofbleeding
Majorbleeding(eg,
intracranial,
retroperitoneal,
compartmentsyndrome,
massivegastrointestinal)
Agent
Dabigatran(Pradaxa)
Possibleinterventions
Idarucizumab
ActivatedPCC*(eg,FEIBA)
Antifibrinolyticagent(eg,tranexamicacid,epsilon
aminocaproicacid)
Oralactivatedcharcoal(iflastdosewithinpriortwo
hours)
Hemodialysis
RBCtransfusionsifneededforanemia
Platelettransfusionsifneededforthrombocytopenia
orimpairedplateletfunction(eg,duetoaspirin)
Surgical/endoscopicinterventionifappropriate
Rivaroxaban(Xarelto),
apixaban(Eliquis),
edoxaban(Lixiana)
4factorunactivatedPCC*(eg,Kcentra)
Antifibrinolyticagent(eg,tranexamicacid,epsilon
aminocaproicacid)
Oralactivatedcharcoal(iflastdoserecentenough)
RBCtransfusionsifneededforanemia
Platelettransfusionsifneededforthrombocytopenia
orimpairedplateletfunction(eg,duetoaspirin)
Surgical/endoscopicinterventionifappropriate
Minorbleeding(eg,
epistaxis,uncomplicated
softtissuebleeding,minor
[slow]gastrointestinal
bleeding)
Dabigatran(Pradaxa)
Localhemostaticmeasures
Possibleanticoagulantdiscontinuation
Halflife(normalrenalfunction ):12to17hours
Possibleantifibrinolyticagent(eg,tranexamicacid,
epsilonaminocaproicacid)
Rivaroxaban(Xarelto),
apixaban(Eliquis),
edoxaban(Lixiana)
Localhemostaticmeasures
Possibleanticoagulantdiscontinuation
Halflives(normalrenalfunction ):
Rivaroxaban5to9hours
Apixaban8to15hours
Edoxaban6to11hours
Possibleantifibrinolyticagent(eg,tranexamicacid,
epsilonaminocaproicacid)
Thetabledescribesmeasuresthatmaybeusedtomanagebleedingassociatedwithdirectoralanticoagulants
(DOACs).ClinicaljudgmentisessentialinallcasesofDOACassociatedbleedinginordertoassesstherisksof
bleedingandweightheseagainsttherisksofthrombosisifanticoagulationisdiscontinuedorreversed.Referto
UpToDatetopicsontheuseofdirectthrombininhibitorsanddirectfactorXainhibitors,andmanagementofDOAC
associatedbleedingforfurtherdetailsanddosing.Theonsetofalloftheagentsdiscussedhereinisapproximately
2to4hours.
DOAC:directoralanticoagulantPCC:prothrombincomplexconcentrateFEIBA:factoreightinhibitorbypassing
activityRBC:redbloodcell.
*UsePCCproductonlyifcontinuedbleedingisreasonablylikelytobefatalwithinhours.
Theanticoagulanteffectoftheseagents(especiallydabigatran)willdissipatemoreslowlyasrenalfunctiondeclines.
Severehepaticfailuremayalsoprolongthehalflifeforrivaroxaban,apixaban,andedoxaban.
23/26
2016.12.02.
Expectedeffectsofanticoagulantdrugsoncommonlyusedcoagulationtests
Drugclass
VitaminK
antagonists
Brand
name(s)
Drug
PT
aPTT
Antifactor
Xaactivity
Warfarin
Coumadin,
Jantoven
/*
Acenocoumarol
Sintrom
/*
Unfractionated
heparin
LMWheparins
Enoxaparin
Lovenox
Dalteparin
Fragmin
Nadroparin
Fraxiparine
Fondaparinux
Arixtra
Directthrombin
inhibitors
Argatroban
Acova
Dabigatran
Pradaxa
DirectfactorXa
inhibitors
Rivaroxaban
Xarelto
Apixaban
Eliquis
Heparins
PTandaPTTaremeasuredinsecondsantifactorXaactivityismeasuredinunits/mL.Upwardarrow()signifies
anincreaseabovenormalduetotheanticoagulant(prolongationofPToraPTTincreaseinantifactorXaactivity).
Theeffectmagnitudewillvarydependingonthereagentformulationandinstrumentused.Dash()signifiesno
appreciableeffect.NormalrangesforthePT,aPTT,andantifactorXaactivityvaryamonglaboratoriesandshould
bereportedfromthetestinglaboratoryalongwiththepatientresult.RefertotheUpToDatetopiconcoagulation
testingfordetails.
PT:prothrombintimeaPTT:activatedpartialthromboplastintimeLMWheparin:lowmolecularweightheparin.
*WarfarinhasaweakeffectonmostaPTTreagents.However,warfarinusewillincreasethesensitivityoftheaPTTto
heparineffect.
Whileheparin,LMWheparin,andfondaparinuxshould,intheory,prolongthePTasindirectthrombininhibitors,in
practicemostPTreagentscontainheparinbindingchemicalsthatblockanyheparineffectbelowaconcentrationof1
unit/mL.Aboveconcentrationsof1unit/mL,heparineffectonthePTmaybeobserved.
AntifactorXaactivitytestingmustbecalibratedforthespecificanticoagulantthisinformationshouldbeverifiedwith
theclinicallaboratory.
24/26
2016.12.02.
PCCproductsavailableintheUnitedStates
Unactivatedprothrombincomplexconcentrates(PCC)
4factor:
ContaincoagulationfactorsII,VII,IX,andXininactiveforms
Kcentra
3factor:
ContainfactorsII,IX,andX(littletonofactorVII)
BebulinVH
ProfilnineSD
Activatedprothrombincomplexconcentrates(aPCC)
4factor:
ContainscoagulationfactorsII,VII,IXfactorVIIismostlyactivated*
FEIBANF
Thetablelists4factorand3factor(whichcontainlittletonofactorVII)PCCproductsavailableintheUnited
States.PCCsalsocontainproteinsCandS,andsomecontainheparinfromthepurification.Unactivatedfactors
areproenzymes(inactiveprecursorproteins).Activatedfactorshavehigherenzymaticactivity.RefertoUpToDate
topicsonwarfarinreversalforuseoftheseproducts.KcentraissoldinCanadaasOctaplex.
PCC:prothrombincomplexconcentratesFEIBANF:factoreightinhibitorbypassingactivity,nanofiltered.
*AsinglefactorproductcontainingrecombinantactivatedhumanfactorVII(rFVIIa)isalsoavailable.
25/26
2016.12.02.
ContributorDisclosures
DavidAGarcia,MD Grant/Research/ClinicalTrialSupport:DaiichiSankyo,Janssen/Bayer[anticoagulants
(edoxaban,rivaroxaban)].Consultant/AdvisoryBoards:BMS,Pfizer,BoehringerIngelheim[anticoagulants
(apixaban,dabigatran,idarucizumab)]. MarkCrowther,MD,MSc Consultant/AdvisoryBoards:Portola,
BoehringerIngelheim[anticoagulationreversal(andexanet,idarucizumab]). LawrenceLKLeung,
MD Nothingtodisclose MariaEMoreira,MD Nothingtodisclose JenniferSTirnauer,MD Nothingto
disclose
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmustconform
toUpToDatestandardsofevidence.
Conflictofinterestpolicy
26/26

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