7/9/2017 Diagnosis of hemolytic anemia in the adult - UpToDate

OfficialreprintfromUpToDate
www.uptodate.com2017UpToDate

Diagnosisofhemolyticanemiaintheadult

Author: StanleyLSchrier,MD
SectionEditor: WilliamCMentzer,MD
DeputyEditor: JenniferSTirnauer,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2017.|Thistopiclastupdated:Jul18,2016.

INTRODUCTIONHemolyticanemiaisdefinedasanemiaduetoashortenedsurvivalofcirculatingred
bloodcells(RBCs)duetotheirprematuredestruction.Therearenumerouscausesofhemolyticanemia,
includinginheritedandacquiredconditions,acuteandchronicprocesses,andmildtopotentiallylife
threateningseverity.Occasionallythecausewillbeobviousfromthehistory,physicalexamination,orfindings
ontheperipheralbloodsmear,butoftentheultimatediagnosisrequiresasynthesisofallofthisinformation
andadditionallaboratorytesting.

Thekeyfindingthatsuggestshemolyticanemiaisanincreaseinthereticulocytecountthatisnotexplained
byrecentbleedingorrecentcorrectionofirondeficiencyorothernutrientdeficiency.Patientsmayalsohave
evidenceofRBCdestructionincludingincreasedlactatedehydrogenase(LDH)andbilirubin,decreased
haptoglobin,andspherocytesontheperipheralbloodsmear.

Thecausesofhemolyticanemiaandadiagnosticapproachtotheadultwithunexplainedhemolyticanemia
arediscussedhere.Othertopicreviewspresentgeneralapproachestodeterminingthecauseofanemiaand
diagnosisofspecifictypesofhemolyticanemia:

Generalapproach,child(See"Approachtothechildwithanemia".)
Generalapproach,adult(See"Approachtotheadultpatientwithanemia".)
Warmautoimmunehemolyticanemia(AIHA),child(See"Autoimmunehemolyticanemiainchildren:
Classification,clinicalfeatures,anddiagnosis".)
WarmAIHA,adult(See"Warmautoimmunehemolyticanemia:Clinicalfeaturesanddiagnosis"and
"Paroxysmalcoldhemoglobinuria".)
Paroxysmalcoldhemoglobinuria(See"Paroxysmalcoldhemoglobinuria".)
Coldagglutinindisease(See"Coldagglutinindisease".)
Hemoglobinopathies(See"Prenatalscreeningandtestingforhemoglobinopathy"and"Clinical
manifestationsanddiagnosisofthethalassemias"and"Diagnosisofsicklecelldisorders".)
Druginducedhemolyticanemia(See"Hemolyticanemiaduetodrugsandtoxins".)
RBCmembranedefects(See"Hereditaryspherocytosis:Clinicalfeatures,diagnosis,andtreatment"
and"Hereditaryelliptocytosisandrelateddisorders"and"Stomatocytosisandxerocytosis".)
RBCenzymaticdefects(See"Diagnosisandmanagementofglucose6phosphatedehydrogenase
deficiency"and"Pyruvatekinasedeficiency".)
Microangiopathichemolyticanemia(MAHA)suchasthromboticthrombocytopenicpurpura(TTP),
hemolyticuremicsyndrome(HUS),ordruginducedthromboticmicroangiopathy(DITMA)(See
"ApproachtothepatientwithsuspectedTTP,HUS,orotherthromboticmicroangiopathy(TMA)".)
Hemolysisassociatedwithbloodtransfusion(See"Hemolytictransfusionreactions"and"Approachto
thepatientwithasuspectedacutetransfusionreaction".)
Paroxysmalnocturnalhemoglobinuria(PNH)(See"Clinicalmanifestationsanddiagnosisofparoxysmal
nocturnalhemoglobinuria".)

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RBCTURNOVERINHEMOLYTICANEMIAThetypicallifespanofaredbloodcell(RBC)isapproximately
110to120days(fourmonths).Duringthistime,RBCsaresubjectedtoaremarkableamountofmechanical
stressastheytraversecapillariesandspleniccordsmuchsmallerthantheirdiameter,whichrequires
repeatedcyclesofdeformationandelasticrecoil.Thishappensmanymillionsoftimesoverthecourseofthe
RBClifespan.

ThepropertiesoftheRBCthatallowittowithstandthisstressincludeahighlydeformablemembraneand
underlyingcytoskeleton,anoptimalsurfacetovolumeratio,andanenzymaticsystemthatcontinually
restorestheproperredoxenvironmentofthecell.Theoptimalmembranesurfaceisapproximately40percent
greaterthanthatofaperfectlysphericalcellofequivalentvolume.RBCvolumeisregulatedbyionpumps
andchannelsthatcontroltheentryofwaterandcationsincludingcationssodium,potassium,calcium,and
magnesium.MetabolicenzymesgenerateATPneededbythecationpumps2,3BPG,whichregulates
oxygenuptakeandreleasebyhemoglobinandreducingcapacity(eg,glutathione,NADPH),toprotectthe
oxygenrichRBCfromoxidantinjury[1].

NormalagingofRBCsresultsinagedependentRBCdestruction,referredtoasrandomhemolysis.This
typicallyoccursatarateofapproximately1percentofRBCsdaily.ThepercentageofRBCsthatarecleared
fromthecirculationcanbeincreaseddramaticallyinhemolyticstates,especiallywhenanenlargedspleenis
contributingtohemolysis[2].(See"Redbloodcellsurvival:Normalvaluesandmeasurement".)

HemolysisoccurswhentheRBCisunabletomaintainitsintactstructureduringpassagesthroughthe
circulationandreticuloendothelialsystem.Hemolysisbyanymechanismstimulatesacompensatoryincrease
inRBCproductionviaincreasederythropoietin(EPO)secretionbythekidney.EPOinturnstimulatesthe
bonemarrowtoproducemoreRBCprecursors,whichisfollowedwithinafewdaysbyanincreaseinthe
reticulocytecountandwithinanadditionalonetotwodaysbyanincreaseinthehemoglobinleveland
hematocrit.(See"Regulationoferythropoiesis"and"Approachtotheadultpatientwithanemia",sectionon
'Theredbloodcelllifecycle'.)

Theoccurrenceofanemiaanditsseverityisdeterminedbythebalancebetweentheextentofhemolysisand
thecapacityofthebonemarrowtoamplifyRBCproduction.Thisbalanceisillustratedinthefollowing
calculationsandclinicalexamples:

RBCsurvivalandturnoverratecanbecalculatedundersteadystateconditions(eg,whenthesecretion
andresponsetoEPOareintact)fromthepercentageofreticulocytesandthereticulocytelifespan(RLS).
TheRLSincreasesproportionallyasthehematocritdecreasesandreticulocytesenterthecirculationat
progressivelyearlierstagesintheirmaturation(whenthehematocritislower,reticulocytesarereleased
earlierfromthebonemarrow).InthesteadystatewithoutanemiathetypicalRLSisapproximatelyone
day,afterwhichthecellbecomesamatureRBC.Insevereanemia,reticulocytescanbereleasedfrom
thebonemarrowasmuchas1.5daysearly("shiftcells"),givingaRLSof2.5days.

RBCsurvivalRBCsurvival(days)100[Reticulocytes(percent)RLS(days)]

TheRLSis1.0,1.5,2.0,or2.5daysathematocritsof45,35,25,and15percent,respectively(figure
1).Foranindividualwithouthemolysiswhohasahematocritof40andareticulocytecountof1
percent,RBCsurvivaliscalculatedtobeapproximately100days(100[11]=100).Corrections
fortheincreasedRLScanbemadeinpatientswithsevereanemiatoreflectthedegreeof
reticulocytosismoreaccurately.(See'Highreticulocytecount'below.)

RBCturnoverTherateofRBCturnoveristhereciprocalofRBCsurvival:

RBCturnoverrate(percent/day)=100RBCsurvival(days)

Inadults,thenormalrateofRBCturnoverisapproximately1percentperday,andthemaximal
sustainablecapacityofthebonemarrowtoincreaseRBCproductioninanadultisapproximately5

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percentperday(ie,approximatelyfivetimesnormal).Inchildren,thebonemarrowcapacitycan
increaseRBCproductionuptoeighttimesnormal.

Inanadultwithsicklecellanemiawhohasahematocritof26percentandareticulocytecountof15
percent,theestimatedRBCsurvivalis13days(100[152]),andtherateofRBCturnoveris7.7
percent/day(10013=7.7percent).Thisturnoverrateexceedsthecapacityoftheindividual'sbone
marrowtocorrecttheanemiacompletely,whichiswhythehematocritisonly26percent.Statedanother
way,theindividual'sbonemarrowcanonlydeliver65percentoftheneededRBCs(57.7=0.65)65
percentofthenormalhematocritof40percentgivesahematocritof26percent.Further,ifthisindividual
weretodeveloptransientbonemarrowaplasia(eg,duetoparvovirusinfection),thenthehematocrit
wouldfallbyapproximately7.7percentperday.Aftersevendays,thehematocritwillhavefallenby
approximatelyhalftogiveahematocritof13percent,withsevereclinicalconsequences.Incontrast,ifan
individualwithoutongoinghemolysisweretodevelopparvovirusinfectionandhavesevendaysofbone
marrowaplasia,thehematocritwouldonlydecreaseby7percent,whichislikelytobeclinicallysilent.

Reticulocytosisrequiresadequateironandvitamins(B12,folate)forRBCproduction,alongwithanormally
functioningbonemarrowandadequateerythropoietinproduction.Thus,individualswhoaredeficientiniron,
vitaminB12,orfolatethosewithconcomitantbonemarrowabnormalities(eg,frominfectionorprimarybone
marrowdisorders)andthosewithinadequateerythropoietinproduction(eg,fromchronickidneydisease)
maynothavereticulocytosis.(See'Hemolysiswithoutreticulocytosis'below.)

Additionalinformationaboutthepathogenesisofspecifictypesofhemolyticanemiaarediscussedinseparate
topicreviews.(See"Pathogenesisofautoimmunehemolyticanemia:Warmagglutininsanddrugs"and
"Pathogenesisofautoimmunehemolyticanemia:Coldagglutinindisease"and"Hereditaryspherocytosis:
Mechanismofhemolysisandpathogenesis"and"Pathogenesisofparoxysmalnocturnalhemoglobinuria"and
"Pathophysiologyofbetathalassemia"and"Pathophysiologyofalphathalassemia".)

CONCEPTUALFRAMEWORKCausesofhemolysiscanbecategorizedinvariousways,including
whethertheabnormalityisintrinsicorextrinsictotheredbloodcell(RBC)(intracorpuscularversus
extracorpusculardefects),whethertheconditionisinheritedoracquired,whetherthehemolysisisacuteor
chronic,whetherthemechanisminvolvesimmunedestructionduetoantibodies(immuneversusnonimmune
mechanism),andwhetherthehemolysisoccursinthevasculatureorinthereticuloendothelialmacrophages
intheliverandspleen(intravascularversusextravascularhemolysis).Mostoftheinheritedconditionsare
intracorpuscular,andmostofthehemolysisbyanimmunemechanismisextravascular.

IntracorpuscularversusextracorpusculardefectsClassifyinghemolyticanemiasaccordingtowhether
thedefectresideswithintheRBCitself(intracorpuscular)versusexternaltotheRBC(extracorpuscular)is
helpfulbecauseitincorporatesthepatienthistoryitalsoallowsthecliniciantodeterminewhetherthe
hemolysisisreversible,whethertransfusedRBCswillalsobeaffected,andwhetherthetreatmentshouldbe
directedataspecificRBCdefectoratanothercondition(eg,aninfectionordrug).

Thetableliststhecausesofhemolyticanemiaclassifiedbywhetherthedefectisintracorpuscularor
extracorpuscular(table1).

Intracorpusculardefectscanaffect:hemoglobinstructureandfunction,membranestructureandfunction,
andcytoplasmiccompositionincludingcontrolofRBCvolumeandredoxpotential.(See'Intracorpuscular
defects'below.)

Extracorpusculardefectsarethoseinwhichexternalfactorsleadtoprematurelossofmembrane,
membranestructuraldamage,volumegainorloss,changesinthesolubilityofhemoglobin,andchanges
intheredoxstateofcellularproteins.(See'Extracorpusculardefects'below.)

IntracorpusculardefectsIntrinsic(intracorpuscular)RBCdefectsarethoseinwhichthepropertiesof
theRBCareresponsibleforhemolysis.Thesedefectsincludethefollowingthreemajorcategories[3,4]:

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HemoglobinopathiesHemoglobinopathiesincludesicklecelldisease(SCD),thalassemia,and
unstablehemoglobinsvariants.Theseaffectthesolubilityofhemoglobin.Whenhemoglobinbecomes
insoluble,itcanprecipitateanddamagetheRBCmembrane.Someabnormalhemoglobinsarelessable
torecoverfromoxidantchallenge,leadingtotheformationofHeinzbodies,asinHgbKln.(See
"Diagnosisofsicklecelldisorders"and"Clinicalmanifestationsanddiagnosisofthethalassemias"and
"Unstablehemoglobinvariants".)

RBCmembrane/cytoskeletaldefectsDisordersthataffectthestructureoftheRBCmembraneand
underlyingcytoskeletonincludehereditaryspherocytosis(HS),hereditaryelliptocytosis(HE),and
hereditarystomatocytosis(HSt).Theseconditionsmaybeassociatedwithasuboptimalmembrane
surfaceareatovolumeration(eg,HS),oradefectinamembraneproteinwithionchannelfunctionsuch
asBand3mayaltersaltandwaterhandling,whichalsocontributestoalteredsurfacemembraneto
volumeratio.(See"Hereditaryspherocytosis:Clinicalfeatures,diagnosis,andtreatment"and"Hereditary
elliptocytosisandrelateddisorders"and"Stomatocytosisandxerocytosis".)

RBCmetabolicabnormalitiesMetabolicabnormalitiesincludedeficiencyofglucose6phosphate
dehydrogenase(G6PD),pyruvatekinase(PK),and,insomecases,HSt.Thesedefectsaffectthe
metaboliccapacityoftheRBC,whichpromotessolutetransportandrecoveryfromoxidantdamage.(See
"Diagnosisandmanagementofglucose6phosphatedehydrogenasedeficiency"and"Pyruvatekinase
deficiency"and"Stomatocytosisandxerocytosis".)

ThevastmajorityoftheintracorpuscularRBCdefectsareinheritedandthemajorityoftheinheriteddefects
areintracorpuscular.Exceptionsincluderareconditionssuchasparoxysmalnocturnalhemoglobinuria(PNH),
anacquiredintracorpusculardefectcausedbyexpansionofacloneofRBCsthatarehypersensitiveto
complementlysisacquiredalphathalassemiainthesettingofmyelodysplasia,anacquiredintracorpuscular
defectcausedbyexpansionofacloneofRBCsthatharboranalphaglobingenemutationandhereditary
TTP,aninheritedextracorpusculardefectinwhichabnormalitiesinthemicrovasculatureleadtoepisodesof
microangiopathichemolysis.(See"Clinicalmanifestationsanddiagnosisofparoxysmalnocturnal
hemoglobinuria"and"Clinicalmanifestationsanddiagnosisofthemyelodysplasticsyndromes"and
"Hereditarythromboticthrombocytopenicpurpura(TTP)".)

ExtracorpusculardefectsExtrinsic(extracorpuscular)RBCdefectsarethoseinwhichtheRBCsare
normalbutaredestroyedduetomechanical,immunologic,infectious,ormetabolic/oxidantdamage.These
abnormalitiesarealmostalwaysacquired.Themajorextracorpuscularcausesofhemolysisinclude:

AntibodiesdirectedagainstRBCmembranecomponents(eg,autoimmunehemolyticanemia[AIHA],
alloimmunehemolyticanemia,acutehemolytictransfusionreaction[AHTR],delayedhemolytic
transfusionreaction[DHTR],somedruginducedhemolyticanemias).(See"Pathogenesisofautoimmune
hemolyticanemia:Warmagglutininsanddrugs"and"Pathogenesisofautoimmunehemolyticanemia:
Coldagglutinindisease"and"Immunologictransfusionreactions".)

Stasis,trapping,anddestructionofRBCinanenlargedspleen(hypersplenism).Thespleenisalsothe
majorsiteofremovalofwarmantibodycoatedredcellsandmostoftheintracorpusculardefects.(See
"Extrinsicnonimmunehemolyticanemiaduetomechanicaldamage:Fragmentationhemolysisand
hypersplenism".)

MechanicaltraumatotheRBCssecondarytohighvelocityjets(malfunctioningcardiacvalves,ventricular
assistdevices)fibrinstandsacrossvesselsthatshearRBCsindisseminatedintravascularcoagulation
(DIC)orplateletmicrothrombiinTTP,hemolyticuremicsyndrome(HUS),ordruginducedthrombotic
microangiopathy(DITMA).(See"Extrinsicnonimmunehemolyticanemiaduetomechanicaldamage:
Fragmentationhemolysisandhypersplenism",sectionon'Malfunctioningcardiacvalvesandcardiac
assistdevices'and"Clinicalfeatures,diagnosis,andtreatmentofdisseminatedintravascularcoagulation
inadults"and"PathophysiologyofacquiredTTPandotherprimarythromboticmicroangiopathies
(TMAs)".)

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Exposuretocompoundswithoxidantpotential(eg,anilinedyes,dapsone,phenazopyridine)inindividuals
withanunderlyingmetabolicdefectsuchasG6PDdeficiency,congenitalmethemoglobinemia,or
unstableHgbvariants(eg,sulfonamides),aswellasthosewithoutanunderlyingdefect.(See"Diagnosis
andmanagementofglucose6phosphatedehydrogenasedeficiency"and"Unstablehemoglobin
variants"and"Geneticsandpathogenesisofmethemoglobinemia".)

AdministrationofRho(D)immuneglobulintoanRh(D)positiveindividual(eg,fortreatmentofimmune
thrombocytopenia)oradministrationofintravenousimmuneglobulin(IVIG).(See"Immune
thrombocytopenia(ITP)inadults:Initialtreatmentandprognosis",sectionon'AntiD'and"Intravenous
immuneglobulin:Adverseeffects",sectionon'Hemolysis'.)

DestructionofRBCbypathogens(eg,malaria,babesiosis,bartonellosis,clostridiumperfringens)(picture
1).(See"Extrinsicnonimmunehemolyticanemiaduetosystemicdisease".)

Lesscommoncausesincludesnakeandinsectbites,certaintoxins,thermalburns,andcopperpoisoning
(eg,Wilsondisease).Althoughrare,Wilsondiseaseshouldbeconsideredineverychildandyoungadult
presentingwithhemolyticanemia,sincethiscomplicationcanbefatal[5].(See"Hemolyticanemiadueto
drugsandtoxins".)

ImmuneversusnonimmuneImmunehemolysisgenerallyreferstoRBCdestructionbyantibodies
and/orcomplementproteinsboundtotheRBCsurface.Immunehemolysisischaracterizedbyapositive
directantiglobulintest(DATalsocalleddirectCoombstest)and/orapositiveindirectantiglobulintest(also
calledindirectCoombstest,or,inthesettingofpretransfusiontesting,referredtoasanantibodyscreen).This
distinctionisusefulclinicallybecauseitimpliesapotentialneedtoremoveanimmunestimulusand/orto
administeratherapydirectedattheimmuneresponse(inAIHA),oranincompatibilityoftransfusedRBCs
withthepatient'simmunesystem(inalloimmuneprocesses).

CommoncausesofimmunemediatedhemolysisincludeAIHA,druginducedhemolysis,andhemolytic
transfusionreactions.Lesscommoncausesofimmunehemolysisincludeparoxysmalcoldhemoglobinuria
andcoldagglutinindisease(table2).(See"Paroxysmalcoldhemoglobinuria"and"Coldagglutinindisease"
and"Pathogenesisofautoimmunehemolyticanemia:Coldagglutinindisease".)

SiteofRBCdestructionThesiteofhemolysiscanbeintravascular(withinthecirculation)or
extravascular(viathereticuloendothelialmacrophagesandmonocytesoftheliverspleen,bonemarrowand
lymphnodes).Thesiteofhemolysisinfluencestheresultsofcertaindiagnostictestsandoftendeterminesthe
clinicalseverityandimmediatemanagementneedsofthepatient.ThisisbecausethesiteofRBCdestruction
determineswhetherthebyproductsofRBCdestructionsuchasfreehemoglobinwillberoutedthroughthe
reticuloendothelialsystemorwillbeliberateddirectlyintothecirculation.

Ifproductsofhemolysisareliberatedintothecirculation,theywillappearasfreeserumhemoglobinor
hemeandurinaryhemoglobin,heme,orhemosiderin.Theserumandurinemaybepinkordarkerbrown.
(See'Diagnosticapproach'below.)

Freehemoglobinorhemeinthecirculationcancausesignificantdamagetothekidney,causingacute
renalfailure,andcantriggerDICorincreasetheriskofthrombosis[6,7].(See'Immediatemanagement
issuesbeforethecauseisidentified'belowand'Thromboticcomplications'below.)

ThemajordeterminantofthesiteofRBCdestructionistheseverityoftheRBCmembranedefectandthe
meansofRBCdestruction.Asanexample,RBCdestructioninAIHAisgenerallyextravascular,as
reticuloendothelialmacrophagesprogressivelyphagocytizesmallpiecesofRBCmembranethatare
opsonizedwithautoantibodies.Incontrast,inhemolysisfrommechanicaltrauma(eg,prostheticheartvalve,
marching,bongodrums),thelysiscanbeimmediateandcompletewithinthecirculation,beforetheRBCs
reachthereticuloendothelialsystem.Likewise,inconditionsinwhichthemembraneattackcomplex(MAC)of
complementcreatesaholeintheRBCmembrane(eg,paroxysmalnocturnalhemoglobinuria[PNH],
paroxysmalcoldhemoglobinuria[PCH]),alargecomponentofintravascularhemolysisislikely.

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However,inmanycasesthereisacomponentofbothintravascularandextravascularhemolysis,especially
whenhemolysisissevere.ThesiteofRBCdestructionthusishelpfulindeterminingthecauseofhemolysis
andtheneedformoreaggressivetherapybuttypicallyisnotdiagnosticofaspecificcondition.

IntravascularhemolysisIntravascularhemolysisreferstohemolysisthatoccursprimarilywithinthe
vasculature.ThisoccurswhenthereisaconsiderableamountofstructuraldamagetotheRBCmembrane
(eg,mechanicalshearing,complementMAC)orwhenthereticuloendothelialsystembecomesoverwhelmed.
Whensevere,intravascularhemolysisischaracterizedbypinkorbrownserumanddarkurinewithfreeserum
andurinehemoglobin[8].Thepinkcolorisduetooxyhemoglobinandthebrownishcolorisduetothe
oxidizedform,methemoglobin.Freehemoglobinbindstohaptoglobin,andthehemoglobinhaptoglobin
complexisrapidlyremovedbytheliver,leadingtoareductioninplasmahaptoglobin,oftentoundetectable
levels(see'HighLDHandbilirubinlowhaptoglobin'below).Dimersofalphabetaglobinthatarenotbound
byhaptoglobinaresmallenough(molecularweight34,000daltons)tobefilteredbytheglomerulusand
appearintheurineashemoglobinuria.

Urinehemosiderinmaybeseenseveraldaysafteranepisodeofintravascularhemolysis,asrenaltubular
cellstakeuptheheme,degradeit,storeitashemosiderin,andeventuallyareshedintotheurine.Urine
hemosiderinisdetectedusingPrussianbluestaining(ironstain)oftheurinesediment.(See'Immediate
managementissuesbeforethecauseisidentified'below.)

Causesofintravascularhemolysisincludethefollowing(table1):

Directtrauma,asinbongodrummersandmarchhemoglobinuria(runners'orfootstrikehemolysis)
Shearstress,asindefectivemechanicalheartvalves
Heatdamage,asinthermalburns
Complementinducedlysis,asinparoxysmalcoldhemoglobinuria
Osmoticlysisfollowinginfusionofhypotonicsolutions
Lysisfrombacterialtoxins(eg,clostridialsepsis)
Lysisfromexposuretohighconcentrationsofcopper
Thromboticmicroangiopathies(TMA)includingTTP,HUS,ordruginducedTMA
Acutehemolytictransfusionreaction
AdministrationofRho(D)immuneglobulintoRh(D)positiveindividuals,suchasfortreatmentofimmune
thrombocytopenia(ITP)
Immunehemolysisthatoverwhelmsthereticuloendothelialsystem

ExtravascularhemolysisExtravascularhemolysisreferstohemolysisthatoccursprimarilyvia
macrophagesofthereticuloendothelialsystemintheliver,spleen,bonemarrow,andlymphnodes.Severely
damagedRBCs,especiallythosecoatedwithcomplement,areprimarilydestroyedintheliver,anorganthat
receivesalargerproportionofthecardiacoutputthanthespleen.PoorlydeformableRBCssuchas
spherocytesorsickledcellsareprimarilydestroyedinthespleen,inthecordsofBillroth.Theseunique
vascularchannelsendblindly,unlikeothervascularchannelsinthebody.TheonlywayforaRBCwitha
diameterof7to8micronstoescapefromthesecordsandreturntothegeneralcirculationistodeform
sufficientlytopassthrough2to3micronslitsinthewallsofthecords(picture2).Senescentordamaged
RBCsremaininthecordsandarephagocytosedbymonocytesandmacrophages.

RBCsdestroyedinthespleenareusuallyphagocytosedintheirentiretyanddigestedwithinphagosomesof
macrophages.Mostofthehemoglobinisdegradedtoreleaseheme,witheachmoleculeofhemeconverted
toequimolaramountsofbiliverdin,iron,andcarbonmonoxideviatheactionofmicrosomalhemeoxygenase
[912].

Thebiliverdinisimmediatelyreducedtounconjugatedbilirubinbytheenzymebiliverdinreductaseandis
releasedintotheplasma.(See"Bilirubinmetabolism".)

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Undernormalcircumstances,theironisefficientlyreleasedfrommacrophagesintotheplasma,mediated
bytheironexportproteinferroportin.Itistransportedtothebonemarrowandusedintheproductionof
newRBCs.Inpatientswiththeanemiaofchronicdisease/inflammation,ironreleaseisimpaireddueto
theactionofhepcidin,resultinginimpairedironmobilizationfornewRBCproduction.(See"Anemiaof
chronicdisease/inflammation",sectionon'Hepcidin'and"Regulationofironbalance".)

ThecarbonmonoxideformedfromhemebreakdowninitiallybindstothehemoglobinofintactRBCsas
carboxyhemoglobin.Itissubsequentlyreleasedinthepulmonarycapillariesandexcretedintothe
expiredair.

LISTOFCAUSESThemajorcausesofhemolyticanemiaincludethefollowing:

Thromboticmicroangiopathy(TMA)suchasthromboticthrombocytopenicpurpura(TTP)orhemolytic
uremicsyndrome(HUS)
Acutehemolytictransfusionreaction(AHTR)
Disseminatedintravascularcoagulation(DIC)
Clostridialsepsis
RBCparasite(eg,malaria,Babesia)
Druginducedimmunehemolysis
Druginducedhemolysisassociatedwithglucose6phosphatedehydrogenase(G6PD)deficiency
Druginducedthromboticmicroangiopathy(DITMA)
Autoimmunehemolyticanemia(AIHA)
G6PDdeficiency
Pyruvatekinase(PK)deficiency
Betathalassemia
Alphathalassemia
Sicklecelldisease
Unstablehemoglobin
Mechanicalhemolysisfromaorticstenosisorprostheticheartvalve
Mechanicalhemolysisfrommarchingorbongodrumming
Osmoticlysisfromhypotonicinfusion
Snakebite
Paroxysmalnocturnalhemoglobinuria(PNH)
Paroxysmalcoldhemoglobinuria(PCH)
Delayedhemolytictransfusionreaction(DHTR)
Hereditaryspherocytosis(HS)
Hereditaryelliptocytosis(HE)
Hereditarystomatocytosis(HSt)
Hereditaryxerocytosis(HX)

Thesecanbeclassifiedinanumberofways,includingmechanism(intracorpuscularversusextracorpuscular
immuneversusnonimmune),siteofhemolysis(intravascularversusextravascular),andacuity/duration
(acuteversuschronic).(See'Conceptualframework'above.)

DIAGNOSTICAPPROACH

OverviewoftheevaluationRecognizinganddiagnosinghemolyticanemiainpatientswithaclassic
presentationisstraightforward.(See'Testingtodeterminethecauseofhemolysis'below.)

However,formanypatients,theexacttimingoftheonsetofanemiamaybeunclear,theredbloodcell(RBC)
morphologymaybeunrevealing,ortheremaybeseveralpossiblediagnosesunderconsideration.Other

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patientsmayhavemorethanonecauseofanemia,oneofwhichmaybluntthenormalreticulocyteresponse
tohemolysis.(See'RBCturnoverinhemolyticanemia'above.)

Thediagnosisofhemolyticanemiaissuspectedinapatientwithchronicornewonsetsymptomsofanemia
(eg,fatigue,weakness,shortnessofbreath),alowhemoglobinlevel,andanincreasedreticulocytecountthat
isnotexplainedbyacceleratedRBCproductionduetorecentbleedingrepletionofiron,vitaminB12,folate,
orcopperoradministrationoferythropoietin.Additionallaboratorytestingisoftenusedtoconfirmthe
diagnosisofhemolyticanemiaandtodeterminethelikelycause.Testingtoconfirmhemolysismaybedone
simultaneouslywithtestingtodeterminethecause,orsequentially.Insomecases,testingtoconfirm
hemolysismaybeomittedifspecifictestingtodeterminethecauseofhemolysisisrapidlyavailableandlikely
tobedefinitive.(See'Laboratoryconfirmationofhemolysis'belowand'Testingtodeterminethecauseof
hemolysis'below.)

Somepatientswithespeciallysevereanemiaorotherworrisomefindingsmayrequireimmediatelifesaving
interventionsbeforehemolysishasbeendiagnosedand/orthecauseidentified.Importantly,lifesaving
interventionssuchastransfusionforsevereanemiaplasmapheresisforpossiblethrombotic
thrombocytopenicpurpura(TTP)orvigoroushydrationanddiuresisforanacutetransfusionreactionshould
notbewithheldwhileconfirmingthediagnosis.(See'Immediatemanagementissuesbeforethecauseis
identified'below.)

Oncethediagnosisofhemolyticanemiaisrelativelycertain,ourapproachtodeterminingthecauseand
providingimmediateinterventionsisasfollows(algorithm1):

Obtainathoroughhistoryandphysicalexaminationtargetedtopotentialcausesofhemolysis.

Rapidlyidentifyandtriageindividualswithpotentiallylifethreateningconditionsthatrequireurgent
involvementofaspecialist(oftenahematologistortransfusionmedicinephysician),suchasathrombotic
microangiopathies(TMA),disseminatedintravascularcoagulation(DIC),oranacutetransfusionreaction.

Ifthepatienthasaclearhistoryoflifelonganemiaorclassicfindingsontheperipheralbloodsmearthat
suggestoneofthehereditaryhemolyticanemiasduetohemoglobinopathy,metabolicdefect,or
membranedefect,pursuespecifictestingforthelikelycondition.

Forotherpatients,obtainadirectantiglobulin(Coombs)test(DAT)todeterminewhethertheanemiais
immuneornonimmune.

IftheDATispositive,immunehemolysisisthelikelydiagnosis.Somepatientsmayrequireadditional
testingtoidentifyassociatedconditions.

IftheDATisnegative,performspecificdiagnostictestssuggestedbythepatienthistoryandphysical
examination.Thesemaybeobtainedsequentiallyorsimultaneouslydependingontheurgencyofthe
evaluation.

Otherlaboratorytestingthatrevealsoneofthespecificcausesofhemolysisisalsostronglysupportive
andinmanycasessufficientfordiagnosis(see'Testingtodeterminethecauseofhemolysis'below)in
somecasesthismaybeavailableatthetimeoftheinitialevaluationandinothersitmaybeobtainedas
partoftheevaluation.

Hematologicconsultationshouldbeobtainedinvirtuallyallpatientswithanewonsetofhemolysis,since
suddenandlifethreateningworseningofanemiamayoccur,requiringurgentcoordinationbetweentreating
clinicians,clinicalpathologists,andtransfusionmedicineorbloodbankpersonnelforappropriate
management.Hemolysismayalsobethefirstsignofanunderlyingsystemicdisorder(eg,thrombotic
thrombocytopenicpurpura,systemiclupuserythematosus,chroniclymphocyticleukemia)andmayrequirean
urgentinterventiontopreventdeathordiseaserelatedcomplications.

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HistoryandphysicalexaminationAsystematicapproach,startingwithathoroughhistoryandphysical
examinationisthecornerstoneoftheevaluation.Helpfulcluesfromthehistoryandphysicalexamination
includethefollowing,ifpresent:

Rapidonsetofsymptomsofanemiaintheabsenceofbleedingisconsistentwithbriskhemolysis.
Jaundiceisconsistentwithbriskhemolysisthatoverwhelmsthecapacityofthereticuloendothelial
systemtoconvertbilirubintostorageiron.
Darkurineisconsistentwithintravascularhemolysis.
Recentbloodtransfusionsuggestspossibleacutehemolytictransfusionreactiontransfusioninthe
previousfourweeksalsoraisesthepossibilityofadelayedhemolytictransfusionreaction.
Initiationofanewmedicationwithpotentialforcausinghemolysissuggestspossibledruginduced
etiology.
Historyofhemolyticanemiaorunexplainedanemiainfamilymemberssuggestsaninheriteddisorder
thisismorelikelyifmultiplefirstdegreefamilymembersareaffected.
Historyofpigmentedgallstonesorpresenceofgallstonesimplieschronichemolysisthatoverwhelmsthe
reticuloendothelialsystem.
Splenomegalysuggestsexpansionofthereticuloendothelialcapacity.

However,theabsenceofthesefeaturesdoesnoteliminatethepossibilityofhemolyticanemia.Patientswith
chroniccompensatedhemolyticanemiamayhaveminimaltonosymptomsofanemia,anegativefamily
history,nonewdrugs,andnoevidenceofjaundiceorsplenomegaly.

LaboratoryconfirmationofhemolysisThereisnosinglespecificdiagnostictestforhemolyticanemia.
However,mostexpertsconsiderthediagnosistobeacceptedifthereareamajorityofthefollowingfindings:

Anemiathatisnotduetoanotherobviouscause.
IncreasedreticulocytecountthatisnotexplainedbyacceleratedRBCproductionduetorecentbleeding
repletionofiron,vitaminB12,folate,orcopperoradministrationoferythropoietin.
SignsofRBCdestructionsuchasincreasedlactatedehydrogenase(LDH),lowhaptoglobin,increased
unconjugatedbilirubin.

Additionaltestresultsthatareconsistentwithaspecificcauseofhemolyticanemia(eg,schistocytesor
spherocytesonperipheralbloodsmearfreehemoglobinorpinkserumnewlypositivedirectantiglobulin
[Coombs]test[DAT]hemoglobinanalysisdemonstratinganabnormalhemoglobin)arehighlysupportiveand
insomecasesdiagnosticifpresent,buttheirabsencedoesnotexcludethepossibilityofhemolysis.(See
'Testingtodeterminethecauseofhemolysis'below.)

CBC/bloodsmearreviewAllpatientsforwhomthediagnosisofhemolyticanemiaisconsideredwill
havehadacompletebloodcount.Inthemajorityofcases,thiswillincludeawhitebloodcell(WBC)count,
plateletcount,andRBCindices.Hemolysiswillbeassociatedwithsomedegreeofanemiainthemajorityof
cases,especiallywhenitfirstoccurs,whenthereisadelayintheproductionofnewRBCstocompensatefor
hemolysis,and,ifitissevere,whenthebonemarrowcannotfullycompensate.(See'RBCturnoverin
hemolyticanemia'above.)

Inmosttypesofhemolyticanemia,theotherbloodcellcounts(WBCandplateletcount)willbenormal.An
abnormallyhighorlowWBCsuggestsinfectionorhematologicmalignancy.Sepsiscanassociatedwith
hemolysisduetodirectRBClysis(eg,inclostridialsepsis,malaria,bartonellosis,orbabesiosis)orDIC.
Hematologicmalignanciesclassicallyassociatedwithhemolysisincludechroniclymphocyticleukemia(CLL)
withautoimmunehemolysisandacutepromyelocyticleukemia(APL)withDIC.

Inmostcasesofhemolyticanemia,therewillbesomedegreeofmacrocytosis,asreticulocytesarelarger
thannormalRBCs.However,themeancorpuscularvolume(MCV)maybelow,normal,orhighdependingon
thedegreeofreticulocytosisandthepresenceofspherocytesorotherabnormalRBCshapes,asspherocytes
havealowMCVthatmaylowertheaveragecellvolumeintothenormaloreventhelowrange.
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Reviewoftheperipheralbloodsmearisanextremelyvaluabletoolfordeterminingthepresenceandcauseof
hemolyticanemia.Inmanycases,findingsonthebloodsmearareessentialtoprovidinglifesavingtreatment.
Examplesincludethromboticmicroangiopathies(TMAs)suchasthromboticthrombocytopenicpurpura(TTP)
ordruginducedTMA(DITMA)infectionssuchasmalariaorBabesiaandHeinzbodiesorbitecellssuggests
hemolysisduetoanoxidantdruginapatientwithglucose6phosphatedehydrogenase(G6PD)deficiency.

Aninitialevaluationforthecauseofanemiamayhavealreadyoccurredinsomeindividualsforwhomthe
likelihoodofhemolysiswasthoughttobeloworforwhomhemolysiswasnotconsideredinitially.The
discussionhereinpresumesthatothercommoncausesofanemiahavebeenevaluatedorexcludedbasedon
theclinicalhistory,examination,orlaboratorytesting.(See"Approachtotheadultpatientwithanemia".)

HighreticulocytecountAhighreticulocytecountimpliesanacceleratedproductionofRBCsinthe
bonemarrow.Increasedreticulocytesisatypicalfindinginhemolyticanemiabutisnotspecificforhemolysis
thebonemarrowcanalsoincreaseRBCproductioninresponsetobleeding,nutrientrepletion(eg,vitamin
B12,folicacid,iron),orerythropoietinadministration.Theabsenceofreticulocytosisdoesnoteliminatethe
possibilityofhemolysis,assomeindividualshaveconcomitantbonemarrowsuppressionorreducedbone
marrowfunctionthatinterfereswithproductionofreticulocytes.(See'Hemolysiswithoutreticulocytosis'
below.)

Thedegreeofreticulocytosiscanbeestimatedfromtheperipheralbloodsmear,asreticulocytesarelarger
thanmatureRBCs,lackcentralpallor,andhaveabluishtint(polychromasia)(picture3).Thecountcanbe
quantifiedfromamanualcountonaperipheralbloodsmearstainedforreticulin(picture4)orbyan
automatedcounter.Somecountersautomaticallyprovidethereticulocytecount.(See"Automatedhematology
instrumentation",sectionon'Automatedcountingofreticulocytes'.)

ReticulocytescanbeexpressedasapercentageofRBCsorasanabsolutenumberthesenumberscanbe
correctedforthedegreeofanemiaandthelifespanofthereticulocytesinthecirculation.Incasesofmarkedly
increasedreticulocytosisorfailureofthebonemarrowtoproducereticulocytes,anyofthesemeasuresis
likelytobearelativelygoodindicatorofthedegreeofreticulocytosis.However,thecorrectionsmakethe
countmoreaccurate,andinsomecasesareessentialtodeterminingwhetherreticulocytosisistruly
increased:

ReticulocytepercentageThereticulocytepercentageconveysthepercentageofallRBCsthatare
reticulocytes.SinceitisrelativetothetotalRBCcount,itmaybeartificiallyincreasedinsevereanemia
andartificiallydecreasedifthepatientisnotanemic.Thenormalreticulocytepercentageinapatient
withouthemolysisisintherangeof1to2percent.Inpatientswithhemolysisandanotherwiseintact
bonemarrow,reticulocytepercentageisatleast4to5percent,andoftenconsiderablyhigher.Thiswas
illustratedinaseriesof109individualswithautoimmunehemolyticanemia,inwhichthemedian
reticulocytepercentageatdiagnosiswas9percent[13].However,therangewaslarge(0.4to92
percent)andapproximatelyonefifthhadareticulocytepercentage<4percent.

CorrectedreticulocytecountThereticulocytepercentageisarelativenumber.Foranygivennumber
ofreticulocytes,alowerthetotalnumberofRBCs(thedenominator)willraisethepercentageofthese
RBCsthatarereticulocytes.Thus,thereticulocytepercentagecanbemultipliedbythepatient's
hematocritdividedbyanormalhematocrit(eg,45percent)togiveacorrectedreticulocytepercentage.
Asanexample,ifreticulocytesare10percentinapatientwithahematocritof22.5percent,thecorrected
countcanbeobtainedbymultiplying10percentx(22.5percent45percent)=10percentx0.5=5
percent.

AbsolutereticulocytecountTheabsolutereticulocytecounthastheadvantageofaccurately
reflectingthedegreeofreticulocytosisregardlessofthedegreeofanemia[14,15].Thenormalabsolute
reticulocytecountisbetween25,000to75,000/microL(ie,approximately1percentofanabsoluteRBC
countof5,000,000cells/microL).Anexampleoftheutilityofthismeasureisaseverelyanemicpatient
withahematocritof18percent,aRBCcountof2,000,000/microL,andreticulocytecountof3percent.

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Whilethereticulocytecountof3percentappearshigh,theabsolutereticulocytecountisonly
60,000/microL(ie,3percentof2,000,000),whichisinthenormalrange.

CorrectedabsolutereticulocytecountThemoreseveretheanemia,theyoungerthereticulocytes
arewhentheyarereleasedintothecirculation,andhencethelongertheirlifespaninthecirculation.The
absolutereticulocytecountcanbecorrectedforthereticulocytelifespan(RLS),alsocalledthe
reticulocytematurationtime(RMT).TheRLSis1.0,1.5,2.0,or2.5daysathematocritsof45,35,25,and
15percent,respectively(figure1).(See'RBCturnoverinhemolyticanemia'above.)

Inapatientwithahematocritof18percentandanabsolutereticulocytecountof60,000/microL,theRLS
isapproximately2.5daysthus,thecorrectedabsolutereticulocytecountis(60,0002.5=
24,000/microL),whichisinappropriatelylow.

Reticulocyteproductionindex(RPI)TheRPImakescorrectionsforboththehematocritandthe
reticulocytelifespan(calculator1):

RPI=Reticulocytes(percent)x(HCT45)x(1RMT)

TheRPIinanindividualwithouthemolysisorbloodlossisapproximately1.Avalueinexcessof2to3is
consideredincreased,whereasavalue<2inapatientwithanemiaisconsideredinappropriatelylow[13].

Theuseofthereticulocytepercentageandabsolutereticulocytecountarediscussedinmoredetail
separately.(See"Approachtotheadultpatientwithanemia",sectionon'Reticulocytecount'.)

HighLDHandbilirubinlowhaptoglobinTheothermajortypicalfindinginhemolyticanemiaaside
fromreticulocytosisisevidenceofRBCdestructionfrombreakdownproducts.Hemolysisreleaseslactate
dehydrogenase(LDH)andhemoglobinfromRBCs.Hemoglobinisboundbycirculatinghaptoglobin,which
facilitateshemerecyclinghemoglobinisconvertedtobilirubinaspartofthedegradationandhemerecycling
process(figure2).Thus,highLDHandbilirubinandlowhaptoglobinareallconsistentwithhemolysis.
However,thereareseveralcaveats:

LDHandbilirubinHighLDHandbilirubinarenotveryspecificforhemolysis,astherearenumerous
otherpossiblecausesoftheseabnormalities(table3).Whenbilirubinelevationisduetohemolysis,the
elevationispredominantlyintheindirect(unconjugated)bilirubin.(See"Classificationandcausesof
jaundiceorasymptomatichyperbilirubinemia".)

HaptoglobinThenormalrangeforserumhaptoglobiniswide.Alowhaptoglobinislikelytobedueto
hemolysis,andanundetectablehaptoglobinlevelisalmostalwaysduetohemolysis.Inaseriesof100
patientswithvariousmedicalconditions,ahaptoglobinlevelof25mg/dLprovidedthebestcutoff
betweenhemolyticandnonhemolyticdisorders[16].Thesensitivityandspecificityofahaptoglobin25
mg/dLwere83and96percent.However,anormalorincreasedhaptoglobindoesnoteliminatethe
possibilityofhemolysisbecausehaptoglobinisanacutephasereactantthatcanbeincreasedinthe
settingofinflammation(see"Acutephasereactants").Othercausesoflowhaptoglobininclude
abdominaltraumaandcongenitalahaptoglobinemia[17].

However,inoneseriesofreports,thecombinationofanincreasedserumLDHandareducedhaptoglobin
was90percentspecificfordiagnosinghemolysis,whilethecombinationofanormalserumLDHandaserum
haptoglobin>25mg/dLwas92percentsensitiveforrulingouthemolysis[16,18].

ImmediatemanagementissuesbeforethecauseisidentifiedCertainmanagementissuesmayneed
tobeaddressedbeforethespecificcauseofhemolyticanemiaisdefinitivelyestablished.Importantly,life
savinginterventionsshouldnotbedelayedwhileawaitingtheresultsofdiagnostictesting.

RateofhemoglobindeclineItisimportanttohaveasenseoftherateofdeclineinthehemoglobin
levelinordertomanagethepatientproperly.Individualswithaveryslowdeclineinhemoglobinmaybe
abletoadapttoandtoleratesevereanemiawithoutendorganischemia,whereasthosewithbrisk

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hemolysisandarapiddropinhemoglobinlevelmaybequitesymptomaticandrequiremoreaggressive
treatmentandacceleratedevaluation,eveniftheabsolutehemoglobinlevelisnotthatlow.Therateof
declineisassessedbyperformingserialhemoglobinlevels,hematocrits,andreticulocytecounts,withthe
frequencydeterminedbytheclinicalsituation.

TransfusionPatientswithsevereanemiashouldbetransfusedwithRBCs,especiallyifthereisactive
bleeding,symptomsoforganischemia,orongoingbriskhemolysis.Itmaybeappropriatetoobtainapre
transfusionbloodsamplethatcanbestoredforlateranalysis,particularlyifaninheritedcauseof
hemolyticanemiaissuspected.Forpatientswithpossibleimmunemediatedhemolysisforwhom
crossmatchcompatiblebloodcannotbeidentified,blooddesignatedforimmediatereleasecanbe
transfused.ThisandotheralternativessuchasRBCgenotypingorautoadsorptionarediscussedinmore
detailseparately.(See"Pretransfusiontestingforredbloodcelltransfusion",sectionon'Nonroutine
transfusionsituations'and"Theincompatiblecrossmatch",sectionon'Identificationofbloodfor
transfusion'.)

PlasmaexchangeIncasesofpresumedthromboticmicroangiopathy(TMAie,microangiopathic
hemolyticanemiaandthrombocytopenia),diagnostictestingmaytakehourstodays.Theuseof
therapeuticplasmaexchangeforapresumptivediagnosisofthromboticthrombocytopenicpurpura(TTP)
andinformationregardingthediagnosticevaluationarepresentedseparately.(See"Approachtothe
patientwithsuspectedTTP,HUS,orotherthromboticmicroangiopathy(TMA)".)

HydrationandhemodynamicsupportForindividualswithapparentsevereintravascularhemolysis
(eg,acutehemolytictransfusionreaction[AHTR]duetoABOincompatibletransfusion),freehemoglobin
inthecirculationcancauserenalfailure,hypotension,anddisseminatedintravascularhydration.
Aggressivehydrationandothersupportivemeasuresarediscussedseparately.(See"Approachtothe
patientwithasuspectedacutetransfusionreaction",sectionon'Suspectedacutehemolyticreaction'and
"Clinicalfeatures,diagnosis,andtreatmentofdisseminatedintravascularcoagulationinadults",section
on'Treatment'and"Clinicalfeaturesanddiagnosisofhemepigmentinducedacutekidneyinjury".)

TestingtodeterminethecauseofhemolysisInsomeoftheobvious/classicpresentationsofhemolytic
anemia,itmaymakesensetoproceeddirectlytospecificdiagnostictesting(algorithm1):

Anemiaandthrombocytopeniawithnumerousschistocytes(picture5)onthebloodsmear,whichstrongly
suggestsaTMAsuchasTTP,HUS,ordruginducedTMA.(See"Approachtothepatientwithsuspected
TTP,HUS,orotherthromboticmicroangiopathy(TMA)".)

Rapidonsetoffever,backpain,darkurine,andpinkplasmafollowingabloodtransfusion,whichstrongly
suggestsanAHTR.(See"Approachtothepatientwithasuspectedacutetransfusionreaction",section
on'Acutehemolytictransfusionreaction(AHTR)'and"Hemolytictransfusionreactions",sectionon'Acute
hemolyticreactions'.)

Lifelonganemia,splenomegaly,andRBCmorphologytypicalofoneoftheinheriteddisorderssuchas
spherocytes(picture6),elliptocytes(picture7),orstomatocytes(picture8).(See"Hereditary
spherocytosis:Clinicalfeatures,diagnosis,andtreatment"and"Hereditaryelliptocytosisandrelated
disorders"and"Stomatocytosisandxerocytosis".)

Bloodsmearcharacteristicofsicklecelldisease(picture9)orthalassemia(picture10)inapatientfroma
populationwithahighprevalenceofthecondition.(See"Diagnosisofsicklecelldisorders"and"Clinical
manifestationsanddiagnosisofthethalassemias".)

Rapiddropinhemoglobinlevelafterexposuretoadrugknowntocausehemolysisinindividualswith
glucose6phosphatedehydrogenase(G6PD)deficiency(table4).(See"Diagnosisandmanagementof
glucose6phosphatedehydrogenasedeficiency".)

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Inothercases,thecauseofhemolysismaybelessclear.Asexamples,thepresenceofnumerous
spherocytescouldindicateautoimmunehemolyticanemiaorhereditaryspherocytosis.Forsuchindividuals,
weusethedirectantiglobulin(Coombs)test(DAT)todistinguishbetweenhemolysisduetoanimmune
mechanism(eg,AIHA)andhemolysisthatislesslikelytobeduetoanimmunemechanism(algorithm1).For
thosewithanegativeDAT,weperformdirectedlaboratorytestingbasedonthepatientandfamilyhistory
physicalexaminationpaceandseverityofhemolysisandRBCmorphology.(See'Historyandphysical
examination'above.)

Otherfeaturesthatmaybeusefulinnarrowingthediagnosticpossibilitiesincludethefollowing:

Evidenceofintravascularhemolysis(eg,pinkserum,positiveserumfreehemoglobin,positiveurine
dipstickforheme,positiveurineforhemosiderin)suggestsoneofthefollowing:

AHTR
Overwhelmingbacterialinfection(eg,fromclostridiumperfringens)
Paroxysmalnocturnalhemoglobinuria(PNH)
Paroxysmalcoldhemoglobinuria(PCH)

Redtobrownurineinapatientwithanormalplasmacolormaybeduetotransienthemolysis(ifthe
sampleswerenotevaluatedsimultaneously)ortoacauseotherthanintravascularhemolysis(eg,
myoglobinuria,beetingestion).(See"Urinalysisinthediagnosisofkidneydisease",sectionon'Redto
brownurine'.)

Splenomegalysuggestsacongenital,infectious,orneoplasticprocess.(See"Approachtotheadultwith
splenomegalyandothersplenicdisorders".)

Abnormalfindingonbloodsmear:

Spherocytes(picture6),microspherocytes,andelliptocytes(picture7)suggestAIHA,assessedby
DATorhereditaryspherocytosis,assessedbytestsforincreasedosmoticfragilityand/orgenetic
testing.Elliptocytosismayalsosuggestmyelodysplasia,assessedbybonemarrowevaluationwith
chromosomalanalysis.(See"Warmautoimmunehemolyticanemia:Clinicalfeaturesanddiagnosis"
and"Hereditaryspherocytosis:Clinicalfeatures,diagnosis,andtreatment"and"Clinical
manifestationsanddiagnosisofthemyelodysplasticsyndromes".)

FragmentedRBCs(schistocytes,helmetcells)(picture5)suggestmechanicalhemolysisoraTMA.

Acanthocytes(spurcells)(picture11)andtargetcellssuggestliverdisease.(See"Extrinsic
nonimmunehemolyticanemiaduetosystemicdisease",sectionon'Liverdisease'.)

Blisteror"bite"cells(picture12)suggestoxidantinjuryinthesettingofG6PDdeficiency.(See
"Diagnosisandmanagementofglucose6phosphatedehydrogenasedeficiency".)

Redcell"ghosts"(picture1)indicatesevereintravascularhemolysis,mostoftenassociatedwith
overwhelmingbacterialinfection(eg,fromclostridiumperfringens).

Involvementofspecialistswithexpertiseinhemolyticanemias,laboratorydiagnosis,orgenetictestingmay
behelpfulinespeciallychallengingcases.

ATYPICALPRESENTATIONSAnemiaisoftenmultifactorial,andconcomitantdisordersthatbluntthe
normalreticulocyteresponsecancallthediagnosisofhemolyticanemiaintoquestion.(See'Hemolysis
withoutreticulocytosis'below.)

Insomeindividuals,compensationforhemolysismaybesufficienttoraisethehemoglobinintothenormal
range.(See'Hemolysiswithoutanemia'below.)

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Inothercases,anincreasedreticulocytecountinitiallythoughttoindicatehemolysismayinfactbedueto
anothercauseofincreasederythropoiesis.(See'Reticulocytosiswithouthemolysis'below.)

HemolysiswithoutreticulocytosisHemolyticanemiacanbeseenintheabsenceofanappropriate
reticulocyteresponse,oftenresultinginamoreprofounddegreeofanemia[19].Thisoccurswhenthebone
marrowisnotcapableofrespondingappropriatelytoanemia.Ifhemolysisissuspectedorconfirmedbutthe
reticulocytecountisinappropriatelylow,thereareseveralpossibleconcomitantconditionsthatmaybe
responsibleforbluntingthereticulocyteresponse:

Irondeficiency(absoluteorfunctional)(See"Causesanddiagnosisofirondeficiencyandiron
deficiencyanemiainadults"and"Diagnosisofirondeficiencyinchronickidneydisease"and"Treatment
ofanemiainnondialysischronickidneydisease".)

DeficiencyofvitaminB12,folate,orcopper(See"ClinicalmanifestationsanddiagnosisofvitaminB12
andfolatedeficiency"and"Sideroblasticanemias:Diagnosisandmanagement",sectionon'Copper
deficiency'.)

Anemiaofchronicinflammation(anemiaofchronicdisease)(See"Anemiaofchronic
disease/inflammation".)

Alcohol(See"Hematologiccomplicationsofalcoholuse".)

Myelodysplasia,aplasticanemia,orotherprimarybonemarrowdisorder(See"Clinicalmanifestations
anddiagnosisofthemyelodysplasticsyndromes"and"Aplasticanemia:Pathogenesisclinical
manifestationsanddiagnosis".)

Transientredbloodcell(RBC)aplasiaduetoparvovirusinfection,whichtargetserythropoieticprecursor
cells[20,21](See"ClinicalmanifestationsanddiagnosisofparvovirusB19infection".)

Druginducedbonemarrowsuppressionsuchastherapyforchroniclymphocyticleukemia(CLL)[22]
(See"Overviewofthecomplicationsofchroniclymphocyticleukemia",sectionon'Anemia'.)

Othersettingsinwhichthereticulocyteresponsemaybeinappropriatelylowincludeanautoimmune
hemolyticanemiainwhichtheautoantibodyalsotargetsRBCprogenitorcellsinthebonemarrow,ora
transientlagintheproductionofreticulocytesduringthefirstfewdaysofnewonsethemolysis.

HemolysiswithoutanemiaHemolysiswithoutanemiacanbeseenifthebonemarrowcapacityto
increaseRBCproductionissufficienttoovercometheanemiacausedbythehemolysis.(See'RBCturnover
inhemolyticanemia'above.)

Despiteanormalhemoglobinandhematocrit,hemolysiscanstillbedetectedfromincreasedreticulocytosis
andserumLDH,andconcentrations,andreducedserumhaptoglobin.AnestimateofRBCturnoverfromthe
reticulocytecountinnonanemicpatientsshouldyieldavalueof5or8percentperdayinadultsand
children,respectively.

ReticulocytosiswithouthemolysisApatientthoughttohavehemolyticanemiabasedonanincreased
reticulocytecountmayinfacthaveanothercauseofreticulocytosis.Iftheclinicalpictureisnotfullyconsistent
withhemolyticanemiaoraspecificcauseofhemolysiscannotbeidentified,itmaybeappropriatetoevaluate
thepatientforothercausesofreticulocytosissuchas:

Recoveryfromanepisodeofbleedingorongoingbleeding.
Repletionofiron,vitaminB12,orfolateinapatientwhowasdeficient.
Administrationoferythropoietin.
Recoveryfromabonemarrowinsultsuchasaninfection(eg,parvovirus),medication,oralcohol.

THROMBOTICCOMPLICATIONSThereisawellknownassociationbetweenhemolyticanemiaand
thrombosis,whichmaybeseenwitheitherintravascularorextravascularhemolysis.Themechanism(s)are
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notwellunderstood.Postulatedfactorsincludetheeffectsoffreeplasmahemeorhemoglobin,depletionof
nitricoxide(NO),splenectomy,antiphospholipidantibodiesinsomepatientswithautoimmunehemolysis,and
prothromboticchangesinthesurfaceofaffectedRBCs[23].

Managementandpreventionofthrombosisinspecificdiseasesettingsisdiscussedinseparatetopicreviews:

Paroxysmalnocturnalhemoglobinuria(PNH)(See"Pathogenesisofparoxysmalnocturnal
hemoglobinuria",sectionon'Thrombosis'and"Clinicalmanifestationsanddiagnosisofparoxysmal
nocturnalhemoglobinuria",sectionon'Thrombosis'.)

Sicklecelldisease(SCD)(See"Overviewofthepulmonarycomplicationsofsicklecelldisease",
sectionon'Venousthromboembolismandpulmonarythrombosis'.)

Autoimmunehemolyticanemia(AIHA)(See"Warmautoimmunehemolyticanemia:Clinicalfeatures
anddiagnosis",sectionon'Venousthromboembolism'.)

Hereditaryspherocytosis(HS)(See"Hereditaryspherocytosis:Clinicalfeatures,diagnosis,and
treatment",sectionon'Arterialandvenousthromboembolism'.)

SOCIETYGUIDELINELINKSLinkstosocietyandgovernmentsponsoredguidelinesfromselected
countriesandregionsaroundtheworldareprovidedseparately.(See"Societyguidelinelinks:Anemiain
adults".)

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"
and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto
6thgradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven
condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easyto
readmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmore
detailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowant
indepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremail
thesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsby
searchingon"patientinfo"andthekeyword(s)ofinterest.)

Basicstopic(see"Patienteducation:Autoimmunehemolyticanemia(TheBasics)")

SUMMARYANDRECOMMENDATIONS

Redbloodcells(RBCs)havepropertiesthatallowthemtoremainintactastheytravelthroughthe
circulationandreticuloendothelialsystem.HemolyticanemiaoccurswhentheRBCisunabletomaintain
itsintactstructure.Thedegreeofreductioninhemoglobinlevelisdeterminedbythebalancebetween
theextentofhemolysisandthecapacityofthebonemarrowtoamplifyRBCproductioninresponse.
Samplecalculationsareprovidedabove.(See'RBCturnoverinhemolyticanemia'above.)

Hemolyticanemiascanbeclassifiedaccordingtowhethertheabnormalityisintrinsicorextrinsictothe
RBC(intracorpuscularversusextracorpusculardefects),whethertheconditionisinheritedoracquired,
whetherthehemolysisisacuteorchronic,whetherthemechanisminvolvesantibodymediated
destruction(immuneversusnonimmunemechanism),andwhetherthehemolysisoccursinthe
vasculatureorinthereticuloendothelialmacrophagesintheliverandspleen(intravascularversus
extravascularhemolysis).(See'Conceptualframework'above.)

Causesofhemolyticanemiaarelistedinthetablesandabove.(See'Listofcauses'above.)

Thediagnosisofhemolyticanemiaissuspectedinapatientwithchronicornewonsetanemiawith
reticulocytosisandnotduetoanotherobviouscause.Thereisnosinglespecificdiagnostictestfor
hemolyticanemia.Mostexpertsconsiderthediagnosistobeacceptedifthereisreticulocytosisnot
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7/9/2017 Diagnosis of hemolytic anemia in the adult - UpToDate

explainedbyrecentbleeding,nutrientrepletion,oradministrationoferythropoietinhighlactate
dehydrogenase(LDH)andbilirubinwithlowhaptoglobinandinsomecasesotherlaboratoryfindings.
Oncethediagnosisofhemolyticanemiaisrelativelycertain,wedeterminethecauseusinginformation
fromthehistoryandphysicalexaminationanddirectedlaboratorytesting(algorithm1).(See'Overviewof
theevaluation'above.)

Certainmanagementissuesmayneedtobeaddressedbeforethespecificcauseofhemolyticanemiais
definitivelyestablished,includingtheneedfortransfusion,plasmaexchange,hydration,and
hemodynamicsupport.Thepaceofthehemolysisandstabilityofthehemoglobinlevelshouldbe
assessed.Lifesavinginterventionsshouldnotbedelayedwhileawaitingtheresultsofdiagnostictesting.
(See'Immediatemanagementissuesbeforethecauseisidentified'above.)

Insomeoftheobvious/classicpresentationsofhemolyticanemia,itmaymakesensetoproceeddirectly
tospecificdiagnostictestingtodeterminethespecificcause.Iftheunderlyingcauseislessobvious,we
usethedirectantiglobulin(Coombs)test(DAT)todistinguishbetweenimmuneandnonimmune
hemolysis,andforthosewithanegativeDAT,weperformdirectedlaboratorytestingbasedonthepatient
andfamilyhistory,physicalexaminationpaceandseverityofhemolysisandRBCmorphology
(algorithm1).Involvementofspecialistswithexpertiseinhemolyticanemias,laboratorydiagnosis,or
genetictestingmaybehelpfulinespeciallychallengingcases.(See'Testingtodeterminethecauseof
hemolysis'above.)

Itispossibletohavehemolysiswithoutreticulocytosis,hemolysiswithoutanemia,andreticulocytosis
withouthemolysis.Settingsinwhichthesefindingsoccurarepresentedabove.(See'Atypical
presentations'above.)

Thereisawellknownassociationbetweenhemolyticanemiaandthrombosis,whichmaybeseenwith
eitherintravascularorextravascularhemolysis.(See'Thromboticcomplications'above.)

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Contributor Disclosures
Stanley L Schrier, MD Nothing to disclose William C Mentzer, MD Equity Ownership/Stock Options:
Johnson & Johnson [Anemia (Erythropoietin)]. Jennifer S Tirnauer, MD Nothing to disclose

Contributor disclosures are reviewed for conicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conict of interest policy

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