1/9/2016

Overviewofhemolyticanemiasinchildren
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Overviewofhemolyticanemiasinchildren
Author
MichaelRecht,MD,PhD

SectionEditor
DonaldHMahoney,Jr,MD

DeputyEditor
CarrieArmsby,MD,MPH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jul2016.|Thistopiclastupdated:Mar15,2016.
INTRODUCTIONAnemiaisamongthemostfrequentlaboratoryabnormalitiesseenbyapracticingpediatrician.
Approximately20percentofallchildrenintheUnitedStatesand80percentofchildrenindevelopingcountrieswillbe
anemicatsometimebeforetheir18thbirthdays[1].Anemiaiscausedbyoneofthreebroadmechanisms:decreased
productionofredbloodcells,increasedlossofredbloodcells,ordestructionofredbloodcells.Worldwide,thevast
majorityofchildhoodanemiasareduetoirondeficiency,duetoeitherinadequatedietaryintakeorbloodloss
associatedwithgastrointestinalinfectionssuchashookworm.However,thehemolyticanemiasareassociatedwith
excessivemorbidityandmortality.
Theapproachtoachildwithhemolyticanemiaisdiscussedhere.Anoverallapproachtotheanemicchild,including
thecharacteristicsthatsuggestahemolyticprocess,isdiscussedseparately.(See"Approachtothechildwith
anemia".)
OVERVIEW
ThehemolyticprocessAfterreleasefromthebonemarrow,mature,nonnucleatederythrocytes(redbloodcells,
RBCs)survivefor100to120daysinthecirculation[2].Inthesteadystate,approximately1percentofthecirculating
erythrocytesaredestroyeddaily(ie,senescentRBCs)andarereplacedbyanequalnumberofnewerythrocytes
releasedfromthebonemarrow(ie,reticulocytes)(picture1andpicture2).Thebasicpathophysiologyofthehemolytic
anemiasisareducederythrocytelifespan,rangingfromnearlynormaltoremarkablyshortened.(See"Redbloodcell
survival:Normalvaluesandmeasurement".)
IncompensationforareducedRBClifespan,thebonemarrowincreasesitsoutputoferythrocytes,aresponse
mediatedbyincreasedproductionoferythropoietin.Asanexample,inadultswithhereditaryspherocytosis,thebone
marrowcanincreaseitsoutputoferythrocytessixtoeightfold.Withthismaximalresponse,erythrocytesurvivalcan
bereducedtoavalueaslowas20to30dayswithouttheonsetofanemia(ie,fullycompensatedhemolysis).The
limitsoferythrocyteproductioninotherhemolyticstateshavenotbeendetermined,particularlyininfantsandchildren,
buttheyprobablyarelowerininfantsthaninadults.(See"Regulationoferythropoiesis".)
AsaresultofincreasedRBCproductioninresponsetohemolysis,thereticulocytecountoftenexceeds2percent,
withanabsolutereticulocytecountusuallygreaterthan100,000/microL[3].Whenachronichemolyticprocessis
present,hyperplasiaoftheerythropoieticmarrowelementsoccurs,withreversalofthemyeloidtoerythroidratiofrom
thenormal3:1to1:1orless(picture3andpicture4).Inthesevere,chronichemolyticprocessesofchildhood(eg,
thalassemiamajor,congenitalspherocytosis,sicklecelldisease),hypertrophyofthemarrowmayexpandthe
medullaryspaces,producingbonychanges,particularlyintheskullandhands[4].(See"Diagnosisofhemolytic
anemiaintheadult"and"Clinicalmanifestationsanddiagnosisofthethalassemias",sectionon'Skeletalchanges'and
"Overviewoftheclinicalmanifestationsofsicklecelldisease",sectionon'Skeletalcomplications'.)
DiagnosticprinciplesAhemolyticprocesscanbemeasureddirectlybydeterminingerythrocytesurvivalor
indirectlyviathepresenceofincreasedlevelsofthemetabolicproductsofhemolysis(eg,increasedindirectbilirubin,
increasedlactatedehydrogenase,reducedhaptoglobin).Alternatively,ahemolyticprocessmaybeinferred,inanon
bleedingpatient,bydocumentationoftheincreaseintheerythrocyteproduction(eg,presenceofreticulocytosis)that
usuallyaccompanieshemolyticstates.However,reticulocytosismayalsobeseeninsomenonhemolyticconditions
suchastherecoveryphaseafteranaplasticevent(eg,aftertransienterythroblastopeniaofchildhood,TEC)orchild
withanemiacausedbyironorvitaminB12deficiency,whoisrespondingtotreatment.(See"Redbloodcellsurvival:
Normalvaluesandmeasurement",sectionon'Estimationofredcellsurvivalfromthereticulocytecount'.)
Elevationsofunconjugatedbilirubinoftenoccurinchildrenwithhemolyticanemias.However,overtclinicaljaundice
maybeabsentormaybemissed.Inaddition,totalbilirubinlevelsinexcessof5mg/dLareunusualifhepaticfunction
isnormal.Theincreasedexcretionofbilirubinpigmentsthatoccursinpatientswithchronichemolysisalsomayleadto
theproductionofpigmentedgallstonesthatmaydevelopinearlychildhood[5].(See"Bilirubinmetabolism"and

https://www.uptodate.com/contents/overviewofhemolyticanemiasinchildren?topicKey=PEDS%2F5932&elapsedTimeMs=5&source=machineLearning

1/9

1/9/2016

Overviewofhemolyticanemiasinchildren

"Classificationandcausesofjaundiceorasymptomatichyperbilirubinemia",sectionon'Gallstones'and"Approachto
thechildwithanemia",sectionon'Physicalexamination'.)
Inanyhemolyticstate,hemoglobinisreleasedintotheplasma,whereitcombinesirreversiblywithserumhaptoglobin.
Thelargehemoglobinhaptoglobincomplexisthenrapidlyclearedfromthecirculationbytheliver.Becausethe
syntheticandbindingcapacitiesofhaptoglobinarelimited,serumlevelsofhaptoglobininhemolysisusuallyareeither
decreased(<20mg/dl)orabsent[6].Loworabsenthaptoglobinisnotnecessarilyareliableindicatorofacute
hemolysis,sincecongenitalhaptoglobindeficiencycanbeashighas30percentinsomeWestAfricanpopulations.
Furthermore,haptoglobinisnotmeasureablebeforetwotothreemonthsofage.
Besidestheseindirectindicatorsofhemolysis,isotopicornonisotopictechniquescanmeasureerythrocytesurvival
directly.Radioactivesodiumchromate(51Cr)mostoftenisusedasanerythrocytetaginadults,whereasnon
radioactivetechniquesusingbiotinareavailableforuseinneonatesandchildren.Ashortenederythrocytesurvivalis
likelywhenthe51CrRBChalflifeisreducedbelow20days(normal:28to37days).However,employingsuch
survivalstudiesinclinicalpracticeisnotnecessary.(See"Redbloodcellsurvival:Normalvaluesandmeasurement",
sectionon'RandomlabelRBCsurvivalmethod'.)
ClassificationThehemolyticdisordersmaybeclassifiedaccordingtowhethertheshortenederythrocytesurvivalis
aresultofanintrinsicabnormalityoftheerythrocyte,oranextrinsicabnormalityactingonanormalerythrocyte(table
1).Thesetwocategoriesarenotmutuallyexclusivebecausesomehemolyticdisordersarecausedbyacombination
ofintrinsicandextrinsicmechanisms.
Intrinsichemolyticanemiasgenerallyresultfrominheritedabnormalitiesofhemoglobin,theerythrocyte
membrane,orintracellularredcellenzymes.Theseincludeconditionssuchassicklecelldiseaseand
thalassemia(whicharediscussedindetailinseparatetopicreviews),hereditaryspherocytosis,elliptocytosisand
stomatocytosis,paroxysmalnocturnalhemoglobinuria,andpyruvatekinaseandglucose6phosphate
dehydrogenasedeficiencies.
Extrinsicdisordersusuallyareacquiredandresultfromforcesoragentsthatimmunologically,chemically,or
physicallydamagetheerythrocyte.Theseincludeautoimmunehemolyticanemias,hypersplenism(eg,from
portalhypertension),andcertainoxidantagentssuchasdapsoneandnitrites.
INTRINSICHEMOLYTICANEMIAS
HemoglobinopathiesThefollowinghemoglobinopathiesarecommoncausesofhemolyticdisease,andare
discussedindetailinseparatetopicreviews:
Thethalassemias(primarilybetathalassemiamajorandhemoglobinHdisease)(See"Clinicalmanifestationsand
diagnosisofthethalassemias".)
Sicklecelldisease(See"Overviewoftheclinicalmanifestationsofsicklecelldisease".)
UnstablehemoglobinssuchascongenitalHeinzbodyhemolyticanemias,hemoglobinHasharon,andhemoglobin
Poole.(See"Unstablehemoglobinvariants".)
HereditaryspherocytosisHereditaryspherocytosis(HS)occurspredominantlyinpersonsofNorthEuropean
ancestry,althoughithasbeenfoundinpatientsofmanyethnicgroups.Thetypicalfeaturesareafamilialhemolytic
anemiaofvariousdegreesofseverity,splenomegaly,andsphericalerythrocytesfoundonthebloodsmear(picture5).
Inapproximatelythreequartersofpatients,pedigreeanalysisindicatesanautosomaldominanttransmission[7].
Sporadicdominantmutationshavebeeninvoked,andautosomalrecessivetransmissionissuggestedinsomecases.
ThegeneforHSislocatedinchromosome8[8].
PathophysiologyAdeficiencyorabnormalityoftheerythrocytemembranestructuralproteinspectrinappears
toaffectmostpatientswithHS[9].Othererythrocytemembranestructuralproteinsthathavebeendemonstrated
toplayaroleinthisdiseaseincludeankyrin,band3,andprotein4.2[10].Theyallhaveincommonarelative
deficiencyofspectrin.Thisdeficiencyisassociatedwithanacceleratedlossoftheerythrocytemembrane,which
reducestheerythrocytesurfacearea.Becausethereisnoconcomitantlossofcellularvolume,theerythrocytes
assumeasphericalshape.Increasedmembranecationfluxalsocanbedemonstrated.(See"Hereditary
spherocytosis:Mechanismofhemolysisandpathogenesis".)
Thespleenisintrinsicallyinvolvedinthehemolyticprocessbecausethespleniccirculationimposesametabolic
stressonspherocyticcells.Thespherocyteisrelativelyrigidandnondeformableandpasseswithdifficulty
throughthespleniccordsandsinuses.Thisresultsintheirsequestrationanddestruction.Thehemolyticprocess
https://www.uptodate.com/contents/overviewofhemolyticanemiasinchildren?topicKey=PEDS%2F5932&elapsedTimeMs=5&source=machineLearning

2/9

1/9/2016

Overviewofhemolyticanemiasinchildren

regressesaftersplenectomy,butbiochemicalandmorphologicabnormalitiespersist[11].(See"Extrinsic
nonimmunehemolyticanemiaduetomechanicaldamage:Fragmentationhemolysisandhypersplenism",section
on'Extravascularnonimmunehemolysisduetohypersplenism'.)
ClinicalpresentationHereditaryspherocytosismaypresentintheneonatalperiodwithanemiaand
hyperbilirubinemiathatmayrequirephototherapyorexchangetransfusion.Alternatively,itmaypresentduring
childhoodoradulthoodwithsplenomegalyorchronicanemia.Thedegreeofanemiavariesconsiderablyin
severitybuttendstobesimilarwithinthesamefamily.Thepatientusuallyhasslightjaundice,andthespleen
almostalwaysispalpablyenlargedaftertwoorthreeyearsofage.Expansionofthemarrowcavitiesoccurstoa
lesserextentthaninthalassemia.Somepatientsarefirstdiagnosedwhentheyexperienceanacuteexacerbation
oftheanemiaduetoanaplastic,hemolytic,ormegaloblasticcrisis.Aplasticcrisesassociatedwithparvovirus
infectionsarethemostseriouscomplicationsduringchildhood[12].(See"Hereditaryspherocytosis:Clinical
features,diagnosis,andtreatment",sectionon'Clinicalpresentation'.)
LaboratoryfindingsIndicatorsofhemolysisincludereticulocytosis,anemia,andhyperbilirubinemia.The
hemoglobinlevelrangesfrom6to10g/dLandthereticulocytecountfrom5to20percent(average10percent).
Thespherocyticerythrocytesaresmallerthannormalerythrocytesandlackthecentralpallorofthebiconcave
disk,butonlyarelativelysmallproportionofthecellsarespherocytic(picture5).Erythroidhyperplasiaispresent
inthemarrow(picture4),buterythrocyteprecursorsarenotspherocytic.
Abnormalityoftheerythrocytecanbedemonstratedbyosmoticfragilitystudies.Whenerythrocytesareplacedin
hypotonicsalinesolutions,waterentersthecells,causingthemtoswell.Thenormalbiconcaveerythrocytecan
increaseitsvolume,butthesphericalcellalreadyhasmaximalvolumeforitssurfaceareaandhemolyzesmore
readily(ie,increasedosmoticfragility)[13].In10to20percentofHScases,theosmoticabnormalitycanbe
demonstratedonlyifthebloodisfirstincubatedat37Cfor24hours[14].(See"Hereditaryspherocytosis:
Clinicalfeatures,diagnosis,andtreatment",sectionon'Specificdiagnostictests'.)
HSmustbedifferentiatedfromothercongenitalhemolyticstates.Familyhistory,bloodsmear,andosmotic
fragilitystudiesofferthemostdiagnosticvalue.Acquiredspherocytosisoftheerythrocytesisseenin
autoimmunehemolyticanemias,inwhichthespherocytosisisoftenmorepronouncedthaninHS,andthedirect
antiglobulintestispositive.Inanewborninfant,differentiatingHSfromhemolyticdiseasesecondarytoABO
incompatibilitymaybedifficult.Aperiodofobservationmaybenecessarytoclarifythediagnosis.
TherapySplenectomyalmostinvariablyproducesaclinicalcureexceptinafewinstancesofsevereHSwith
recessivetransmission[15].Splenectomyshouldbedeferredifpossibleuntilthepatientisatleastfiveorsix
yearsofagebecausesplenicfunctionisimportantinyoungerchildrentoprotectthemfromsepsiscausedby
encapsulatedbacteriasuchaspneumococcus.Supportivecarepriortosplenectomyincludesbloodtransfusions
and/orerythropoietinduringinfancyandfolicacidsupplementation.Ifanemiaissevereenoughtoimpairgrowth
ornormalactivity,theoperationcanbeconsideredearlier.Splenectomypreventsgallstonesandeliminatesthe
threatofaplasticcrisis.(See"Hereditaryspherocytosis:Clinicalfeatures,diagnosis,andtreatment",sectionon
'Treatment'.)
Aftersplenectomy,jaundiceandreticulocytosisdisappear.Thehemoglobinconcentrationbecomesnormal,
althoughthespherocytosisandosmoticfragilityabnormalitiesbecomemorepronounced.Overwhelmingsepsis
aftersplenectomyoccurslessfrequentlyifthesurgeryisdelayeduntilthechildisfiveorsixyearsofage,butthe
febrileasplenicchildmustalwaysbecarefullyandurgentlyevaluatedforsepsis[16].(See"Preventionofsepsis
intheasplenicpatient".)
Immunizationwithpolyvalentpneumococcalvaccineshouldbecompleteatleasttwoweeksbeforesplenectomy
[17].Prophylacticpenicillintherapyaftersplenectomyisadvocatedbysomeauthorities,anditdefinitelyis
indicatediftheoperationisperformedbeforethechildissixyearsofage[18].(See"Preventionofsepsisinthe
asplenicpatient",sectionon'Pneumococcalvaccine'and"Preventionofsepsisintheasplenicpatient",section
on'Antibioticprophylaxis'and"Pneumococcal(Streptococcuspneumoniae)polysaccharidevaccinesinchildren",
sectionon'Indications'and"Pneumococcal(Streptococcuspneumoniae)conjugatevaccinesinchildren",section
on'Indications'.)
HereditaryelliptocytosisHereditaryelliptocytosis(HE)isadominantlyinheritedtraitcharacterizedbylarge
numbersofovalorellipticalerythrocytes(picture6)smallnumbersofovalorellipticalerythrocytesmaybeseenin
numerousconditions,especiallythalassemiaandirondeficiency[19].Inmostpatients,noassociatedhemolysis
occursandthehematologicvalues,includingreticulocytecounts,arenormal.However,inapproximately10percentof

https://www.uptodate.com/contents/overviewofhemolyticanemiasinchildren?topicKey=PEDS%2F5932&elapsedTimeMs=5&source=machineLearning

3/9

1/9/2016

Overviewofhemolyticanemiasinchildren

patientswithellipticalcells,evidenceofhemolysisexists,withhemoglobinlevelsaveraging8to10g/dLand
reticulocytescomprising5to15percentofthecirculatingredcells[20].
PathophysiologyAstructuralabnormalityofspectrinhasbeendescribedinerythrocytesfromsomepatients
withHEwithorwithouthemolysis[21].ThebasisforhemolyticHEandHEwithouthemolysisareunclear.In
mostfamilystudiesofhemolyticHE,oneparenthasellipticalerythrocyteswithouthemolysisandtheother
parentishematologicallynormal.(See"Hereditaryelliptocytosis:Geneticsandpathogenesis".)
ClinicalpresentationHEwithhemolysismaybeassociatedwithneonataljaundice,butcharacteristic
elliptocytosismaynotbeevidentatbirth.Thebloodsmearinsteadshowsbizarrepoikilocytesandpyknocytes,
thelatterbeingdescribedassmall,distorted,irregular,denselystainedredcellswithspinyprojections[22].This
conditionhasbeencalledinfantilepyknocytosis.Theusualfeaturesofachronichemolyticprocess,including
anemia,jaundice,splenomegaly,andosseouschanges,maybeseenlater.Cholelithiasisoccursinlater
childhood.Aplasticcriseshavebeenreported.(See"Hereditaryelliptocytosis:Clinicalfeatures,diagnosis,and
treatment".)
LaboratoryfindingsThemorphologyoftheerythrocytesisthemostimportantdiagnosticfeatureofHE.
Ellipticalcells,characterizedbyalengthmorethan1.5timesthediameter,accountfor15percentto70percent
oftheerythrocytes(picture6).InhemolyticHE,thereticulocytecountisincreased.Erythroidhyperplasiais
evidentinthebonemarrow,buttheerythrocyteprecursorsarenotelliptical.Increasederythrocyteosmotic
fragilityandincreasedthermalinstabilityoccurinhemolyticHE,whichhassometimesledtodesignatingcases
ofhemolyticHEaspyropoikilocytosis.(See"Hereditaryelliptocytosis:Clinicalfeatures,diagnosis,and
treatment",sectionon'Hereditarypyropoikilocytosis'.)
TherapyIfsignificanthemolysisexists,splenectomyusuallyisbeneficial.Erythrocytemorphologyisnot
changedaftertheoperation,anditmaybecomeevenmoreabnormal.(See"Hereditaryspherocytosis:Clinical
features,diagnosis,andtreatment",sectionon'Treatment'.)
HereditarystomatocytosisHereditarystomatocytosisisararehemolyticanemiaassociatedwitherythrocytesthat
areswollenandcupshaped.Onstainedsmears,theyhaveamouthlikeslit(ie,stoma)inplaceoftheusualcircular
centralpallor(picture7).Hemolyticanemiaisassociatedwithextremepermeabilityoftheerythrocytemembraneto
cations.Splenectomymaybeindicated.(See"Stomatocytosisandxerocytosis".)
AbnormalitiesoferythrocyteglycolyticenzymesHemolyticanemiascausedbyinheritedabnormalitiesof
erythrocyteglycolyticenzymesincludepyruvatekinasedeficiency,glucose6phosphatedehydrogenase(G6PD)
deficiency,deficienciesofhexokinase,glucose6phosphateisomerase,phosphofructokinase,aldolase,
triosephosphateisomerase,glyceraldehyde3phosphateisomerase,andphosphoglyceratekinase.Mostareinherited
asautosomalrecessivedisorders.Mostoftheseconditionsaremildanduncommon,withtheexceptionofglucose6
phosphatedehydrogenase(G6PD)deficiency.Thesedisordersarereviewedbrieflyhere,andmoredetailisprovidedin
linkedtopicreviews.
Thisgroupofcongenitalhemolyticanemiasoriginallywasclassifiedasnonspherocyticbecausespherocytic
erythrocyteswerenotfoundandresultsoftheosmoticfragilitytestswerenormal.Adiagnosisisestablishedby
demonstratingreductionoftheenzymeaswellasdecreasedlevelsofglycolyticmetabolitesdownstreamofthe
deficientenzyme.Deficienciesofglycolyticenzymescompromiseadenosinetriphosphategeneration.Themetabolic
energyrequirementsoftheerythrocytescannotbemet,andtheerythrocytelifespanisshortened.
PyruvatekinasedeficiencyAninheriteddeficiencyofpyruvatekinase(PK)isthemostcommonofthe
erythrocyteglycolyticenzymedeficiencies[23].PKactivity,measuredintheerythrocytes,isreducedmarkedly,but
theenzymeactivityinotherbloodcellsandtissuesisnormal.(See"Pyruvatekinasedeficiency".)
PathophysiologyThediseaseiscausedbyhomozygosityforamutantPKgene,resultinginmarkedly
decreasedactivityofanabnormalPKisoenzyme[24].ThePKdeficienterythrocytesaredepletedofadenosine
triphosphate(ATP),andtheirsurvivaliscompromised.Levelsofglycolyticintermediates,especially2,3
diphosphoglycerate(2,3DPG,alsocalled2,3bisphosphoglycerate),areincreasedgreatly.Theincreasein2,3
DPGcausesarightwardshiftoftheoxygendissociationcurvethatmayreducesymptomsoftheaccompanying
anemia.(See"Structureandfunctionofnormalhemoglobins",sectionon'2,3bisphosphoglycerate'.)
HeterozygotesforPKdeficiencyhaveintermediateenzymelevelsandarenotclinicallyaffected.
ClinicalpresentationInPKdeficienthomozygotes,abroadspectrumofclinicalandhematologicfindings
occurs,rangingfromamild,completelycompensatedhemolyticstatetosevereanemia.Anemiaand

https://www.uptodate.com/contents/overviewofhemolyticanemiasinchildren?topicKey=PEDS%2F5932&elapsedTimeMs=5&source=machineLearning

4/9

1/9/2016

Overviewofhemolyticanemiasinchildren

hyperbilirubinemiamayoccurintheneonatalperiod.Intheolderpatient,pallor,scleralicterus,andsplenomegaly
areusualfindings.
LaboratoryfindingsThebloodsmearshowspolychromatophilicerythrocytes(picture1),indicatingan
elevatedreticulocytecount.Afewsmallspiculatederythrocytesareseen,butnoincreasednumberof
spherocytesisfound.Osmoticfragilityisnormal.
TreatmentHyperbilirubinemiaintheneonatalperiodmayrequireexchangetransfusion.Severediseasemay
requirerepeatedtransfusionsforanemiaduringinfancy.Splenectomy,althoughnotcurative,mayimprovethe
anemiaandshouldbeconsideredinpatientswithseveredisease[25].Markedreticulocytosisoccursafter
splenectomy.
Glucose6phosphatedehydrogenasedeficiencyGlucose6phosphatedehydrogenase(G6PD)deficiency
resultsintwokindsofhematologicproblems:
Acommonconditionmanifestedbyacutehemolyticepisodesinducedbyinfectionorcertaindrugs(table2).This
patternischaracteristicofpatientswithClassIIandIIIvariants.
Arare,chronic,nonspherocytichemolyticanemia.ThistypeisknownasaClassIvariant,characterizedby
severedeficiencyofG6PD.
TheG6PDgeneisfoundontheXchromosome.Intheaffectedhemizygousmalesubject,theconditionresultsfrom
inheritanceofoneabnormalG6PDgene.Intheaffectedhomozygousfemalesubject,twoabnormalgenesare
inherited.ThenormalG6PDenzymefoundinmostwhitepopulationsisdesignatedG6PDB+,whereasanormal
isoenzymedesignatedG6PDA+iscommoninblacks.Morethan10distinctenzymevariantsofG6PDhavebeen
documented.(See"Geneticsandpathophysiologyofglucose6phosphatedehydrogenasedeficiency",sectionon
'G6PDanditsvariants'.)
PathophysiologyAmutantenzymecalledG6PDAisfoundinapproximately13percentofblackmenand2
percentofblackwomen.Thisenzymeisunstableandisassociatedwithreducederythrocyteenzymeactivity(5
to15percentofnormal)[26].AffectedpersonsofMediterranean,Arabic,andAsianethnicgroupshaverelatively
highfrequenciesofG6PDdeficiencybecauseofavariantdesignatedasG6PDB[27].IntheMediterranean
variant,theenzymeactivityofthehomozygousfemaleorthehemizygousmalesubjectislessthan5percentof
normal.
G6PD,theratelimitingenzymeofthepentosephosphatepathway,iscrucialforprotectionoftheerythrocytes
fromoxidantstress.InG6PDdeficiency,oxidantmetabolitesofnumerousdrugsresultindenaturationand
precipitationofhemoglobin,causingerythrocyteinjuryandrapidhemolysis.However,theacutehemolysis
occursonlyifthepatientisexposedtooxidantdrugs,suchasnaphthalene,sulfonamides,antimalarials,and
naphthoquinones,ortothefavabean(table2).Thedegreeofhemolysisvarieswiththedrug'santioxidanteffect,
theamountingested,andtheseverityoftheenzymedeficiencyinthepatient.(See"Geneticsand
pathophysiologyofglucose6phosphatedehydrogenasedeficiency"and"Clinicalmanifestationsofglucose6
phosphatedehydrogenasedeficiency".)
LaboratoryfindingsHemoglobinemiaandhemoglobinuriaoccur24to48hoursaftertheingestionofan
oxidantsubstance.Thehemoglobinlevelmaydecreaseacutelytoaslowas2to5g/dL."Bitecells"andHeinz
bodies(picture8)areobservedduringthistime.Heinzbodiesarenotvisibleonstainedbloodsmears,butthey
canbedemonstratedonsupravitallystainedpreparations.Bothdisappearafterthreeorfourdays.Spontaneous
recoveryisusualandisheraldedbyreticulocytosisandanincreaseinhemoglobinconcentration,startingfouror
fivedaysaftertheacutehemolyticepisode.
DiagnosisdependsondirectorindirectdemonstrationofreducedG6PDactivityinerythrocytes.Bydirect
measurement,enzymeactivityinaffectedpersonsislessthan15percentofnormal.Thereductionofenzyme
activityismoreextremeinwhitesandAsiansthaninG6PDdeficientblacks.Shortlyafterahemolyticevent,and
atatimewhenareticulocyteresponsehasoccurred,G6PDactivitymaybenormal,secondarytothefactthat
G6PDactivityishigherinreticulocytes.Arepeatexaminationseveralweekslater,whenthereticulocytosishas
abated,maybenecessaryinordertoconfirmthediagnosis.(See"Diagnosisandtreatmentofglucose6
phosphatedehydrogenasedeficiency".)
TherapyPreventionofhemolysisbyavoidingoxidantdrugsisofparamountimportance.Menandboys
belongingtoethnicgroupsinwhichasignificantincidenceofG6PDdeficiencyoccursshouldbetestedforthe

https://www.uptodate.com/contents/overviewofhemolyticanemiasinchildren?topicKey=PEDS%2F5932&elapsedTimeMs=5&source=machineLearning

5/9

1/9/2016

Overviewofhemolyticanemiasinchildren

defectbeforedrugsthatareknowntobepotentoxidantsaregiven.Afterhemolysishasoccurred,supportive
therapy,includingbloodtransfusionsiftheanemiaissevereandthepatientsymptomatic,isindicated.
OtherglycolyticenzymesDeficienciesofseveralotherglycolyticerythrocyteenzymeshavebeendescribedin
patientswithcongenitalnonspherocytichemolyticanemia.Theyincludedeficienciesofhexokinase,glucose6
phosphateisomerase,phosphofructokinase,aldolase,triosephosphateisomerase,glyceraldehyde3phosphate
isomerase,andphosphoglyceratekinase.
Thesediseasesareextremelyrareandmostaretransmittedasautosomalrecessivetraits.Someofthem,aslisted
below,areassociatedwithneurologicdisease,metabolicmyopathy,andabnormalglycogenmetabolism.(See
"Approachtothemetabolicmyopathies",sectionon'Disordersofglycogenmetabolism'and"Overviewofinherited
disordersofglucoseandglycogenmetabolism".)
Phosphofructokinasedeficiencyametabolicmyopathywithhemolyticanemia.(See"Phosphofructokinase
deficiency(glycogenstoragediseaseVII,Taruidisease)".)
Phosphoglyceratekinasedeficiencycentralnervoussystemdysfunctionwithseizuresandintellectual
disability(mentalretardation)associatedwithnonspherocytichemolyticanemia.(See"Phosphoglyceratekinase
deficiencyandphosphoglyceratemutasedeficiency",sectionon'Phosphoglyceratekinasedeficiency'.)
Aldolasedeficiency(see"Otherdisordersofglycogenmetabolism:GLUT2deficiencyandaldolaseAdeficiency")
Triosephosphateisomerasedeficiencyhemolyticanaemiacoupledwithaprogressive,severeneurologic
disorder[28]
Chronichemolysis,oftenmanifestedininfancy,isacommonfeature.Specificerythrocytemorphologicabnormalities
arenotseen.Diagnosisdependsondemonstrationofreductionofthespecificerythrocyteenzyme.Nospecific
therapyexistssplenectomymayreducetherateofhemolysisinsome,butnotall,ofthesedisorders.
OtherpentosephosphatepathwayenzymesThemostimportantfunctionofthepentosepathwayistoprovide
theNADPH(reducednicotinamideadeninedinucleotidephosphate)necessaryformaintainingglutathioneinthe
reducedstate,essentialforthephysiologicinactivationofoxidantcompounds.Withoutadequatelevelsofglutathione,
whenoxidantdrugsareingested,hemoglobinbecomesdenaturedandprecipitatesintoerythrocyteinclusionscalled
Heinzbodies(picture8).Thesebodiesdamagetheerythrocytemembrane,resultinginacutehemolysis[29].
EXTRINSICHEMOLYTICANEMIASHemolyticanemiascausedbyagentsthatdamagenormalerythrocytesand
leadtotheirprematuredestructionarecategorizedasextrinsic(table1).Theseincludetheautoimmunehemolytic
anemias(warmandcoldreacting),hypersplenism,microangiopathiesincludinghemolyticuremicsyndrome(HUS)and
disseminatedintravascularcoagulation(DIC),paroxysmalcoldhemoglobinuria(PCH),paroxysmalnocturnal
hemoglobinuria(PNH)andWilsondisease.
AutoimmunehemolyticanemiasThemostclearlydefinedoftheseagentsareantibodiesdirectedagainstspecific
intrinsicmembraneantigensthatdamagetheerythrocyteandproducehemolysis,causinganautoimmunehemolytic
anemia(AIHA).Thesedisordersareidentifiedbypositiveresultstothedirectantiglobulintest(alsoknownasthe
Coombs'test),whichdetectsimmunoglobulins(eg,IgGorIgM)orcomponentsofcomplementontheerythrocyte
surface.(See"Autoimmunehemolyticanemiainchildren:Classification,clinicalfeatures,anddiagnosis".)
InprimaryAIHA,redbloodcellautoantibodiesarepresentandcausehemolyticanemia,butnoevidenceofan
underlyingsystemicillnessexists.PrimaryAIHAcanbesubclassifiedaccordingtothecharacteristicsofthe
erythrocyteautoantibodiesandautoantigens,intowarmreactiveAIHA,coldagglutinindisease,orparoxysmalcold
hemoglobinuria(table3).
SecondaryAIHAisanimmunemediatedhemolyticanemiawhichoccursinthesettingofabroadersystemicdisorder,
suchassystemiclupuserythematosusoranotherautoimmunedisorder,malignancy,immunodeficiency,orfollowing
certaininfections(table4).Drugssuchaspenicillin,cephalosporins,andalphamethyldopaevoketheformationof
antibodiesinsomepatients.(See"Autoimmunehemolyticanemiainchildren:Classification,clinicalfeatures,and
diagnosis".)
WarmreactivehemolyticanemiaInwarmreactiveAIHA(warmagglutinindisease),circulatingantibodiesare
directedagainstthepatient'sownerythrocytes.Thefactor(s)evokingsuchanautoimmuneresponseareunknownbut
includeviralinfectionsandoccasionallyspecificdrugs.
ClinicalmanifestationsWarmagglutinindiseasetendstooccurintwoclinicalpatterns(see"Warm
autoimmunehemolyticanemia:Clinicalfeaturesanddiagnosis"):
https://www.uptodate.com/contents/overviewofhemolyticanemiasinchildren?topicKey=PEDS%2F5932&elapsedTimeMs=5&source=machineLearning

6/9

1/9/2016

Overviewofhemolyticanemiasinchildren

PrimaryAIHAUnderlyingdiseaseisabsentinprimaryAIHAalthoughtheanemiaisoftenprecededbya
respiratoryinfection[30].AfulminantdiseasecourseistypicalforprimaryAIHA.Theonsetisacute,with
pallor,jaundice,hemoglobinuria,andsplenomegaly.PatientswithprimaryAIHAtypicallyrespondwellto
corticosteroidtherapy.Completerecoveryischaracteristicandmortalityislow.
SecondaryAIHASecondaryAIHAisassociatedwithunderlyingdiseasesuchaslymphomaor
systemiclupuserythematosus.Amorechronicdiseasecourseistypicalwithhighermortality.
LaboratoryfindingsTheanemiamaybesevere,withhemoglobinlevelsoflessthan6g/dL.Spherocytosis
andpolychromasiaareprominent.Reticulocytosisandnucleatederythrocytesarefound,andleukocytosisis
common.Theplateletcountusuallyisnormaloccasionally,thereisanassociatedimmunethrombocytopenia
(ITP,previouslyknownasidiopathicthrombocytopenicpurpura).Thecombinationofautoimmunehemolytic
anemiaandimmunethrombocytopeniaisknownasEvanssyndrome.(See"Autoimmunehemolyticanemiain
children:Classification,clinicalfeatures,anddiagnosis",sectionon'Evanssyndrome'.)
TheresultofthedirectCoombstestispositive,indicatingthepresenceofantibodiesattachedtothe
erythrocytes.TheseantibodiesbelongtotheIgGclass.Theyoftenarenonspecificpanagglutinins,buttheymay
havespecificityforubiquitousantigensoftheRhsystem(eg,E,LW).Becauseofspontaneouserythrocyte
agglutination,thepatientmaybemistakenlytypedasbloodgroupAB,Rh+[31].Inacute,transientcases,only
complementisfoundontheerythrocytes,chieflytheC3andC4components.InchronicAIHA,apureIgG
Coombs'testsresultisoftenfound.(See"Warmautoimmunehemolyticanemia:Clinicalfeaturesanddiagnosis",
sectionon'Positiveantiglobulin(Coombs)test'.)
TreatmentTransfusionmayberequired,butoffersonlytransientbenefit.Completelycompatiblebloodis
difficulttofind,andgivingbloodthatis"incompatible"asjudgedbythecrossmatchoftenisnecessary.
Prednisoneshouldbeadministeredinadoseof2to4mg/kgPOevery24hours[32].Treatmentshouldcontinue
untilhemolysisdecreases.Thedosecanthenbegraduallyreduced.
Theacuteformofthediseaseusuallyremitsspontaneouslywithinafewweeksormonths,buttheCoombstest
mayremainpositiveforanextendedperiod.Splenectomyandimmunosuppressiveagentsmaybebeneficialin
patientsrefractorytoconventionaltherapy.InAIHAsecondarytolymphomaorlupuserythematosus,thedisease
tendstobechronicandthecourseoftheunderlyingdiseasedeterminestheultimateprognosis.
ColdagglutininhemolyticanemiaLowlevelsofcoldantibodiesmayexistnormally,buttheymayincreaseto
veryhighlevelsaftersomeviralormycoplasmalinfections.Thesehightitersofcoldantibodiesinduceintravascular
hemolysiswithresultinghemoglobinemiaandhemoglobinuria.Becausethehemolysisisprimarilyintravascular,dark
coloredurineismorecommonandsplenomegalyislesscommonthaninwarmreactivedisease.
TheantibodiesoftenhavespecificityfortheIantigenandreactpoorlywithhumancordbloodcellspossessingtheI
antigen[33].TheantibodiesareoftheIgMclassandrequirecomplementforactivity.Spontaneousagglutinationand
rouleauxformationareseenonthebloodsmear(picture9).(See"Pathogenesisofautoimmunehemolyticanemia:
Coldagglutinindisease"and"Clinicalfeaturesandtreatmentofautoimmunehemolyticanemia:Coldagglutinins".)
Patientswithinfectiousmononucleosismaydevelopacutehemolyticanemia.Theantibodiesinthesecaseshaveanti
Ispecificity[34].(See"Infectiousmononucleosisinadultsandadolescents",sectionon'Hematologicabnormalities'.)
ParoxysmalcoldhemoglobinuriaParoxysmalcoldhemoglobinuria(PCH)isarareconditionassociatedwitha
specifictypeofcoldantibody,theDonathLandsteinerhemolysin,whichhasantiPspecificity.Intravascularhemolysis
isprecipitatedbylowenvironmentaltemperature[35].Approximatelyonethirdofcasesinthepastwereassociated
withcongenitaloracquiredsyphilis.PCHnowisseenintwoclinicalsituations:inchildrenfollowingviralinfectionand
inadultsasanautoimmunedisorder.(See"Paroxysmalcoldhemoglobinuria".)
ParoxysmalnocturnalhemoglobinuriaParoxysmalnocturnalhemoglobinuria(PNH)isararechronicanemiawith
prominentintravascularhemolysisthatmayhaveitsonsetinlatechildhood[36].Hemolysisischaracteristicallyworse
duringsleep,andmorninghemoglobinuriausuallyispresent.
TheprimarydefectinPNHresidesinanabnormalsurfaceproteinanchortotheredbloodcellmembrane.This
extracellularanchor,orglycosylphosphatidylinositol(GPI),ismissingfromallcellsinthosepatientsaffectedwith
PNH[37].PNHisaclonalabnormality,withthePIGAgenemutatedinaffectedpatients[38].Thisabnormality
renderserythrocytessusceptibletohemolysisbyserumcomplement.Thehemoglobinuriaisexplainablebecausered
bloodcellsnolongerexpressCD55andCD59,bothofwhicharerequiredforclearanceofrandomlydeposited
complementfactorsfromtheerythrocytemembrane,whichallowschroniccomplementmediatedintravascular
https://www.uptodate.com/contents/overviewofhemolyticanemiasinchildren?topicKey=PEDS%2F5932&elapsedTimeMs=5&source=machineLearning

7/9

1/9/2016

Overviewofhemolyticanemiasinchildren

hemolysis.Infectionstendtotriggerepisodesofhemolysis,althoughfrequentlynoidentifiablereasonexists.In
additiontochronichemolysis,thrombocytopeniaandleukopeniamaydevelop.Somecaseshavebeenfollowedby
aplasticanemia,myelodysplasia,oracuteleukemia.(See"Pathogenesisofparoxysmalnocturnalhemoglobinuria"and
"Clinicalmanifestationsanddiagnosisofparoxysmalnocturnalhemoglobinuria".)
Previously,thediagnosiswassuggestedbyapositiveresultintheacidifiedserum(Hamtest)orthrombinorsucrose
lysistests.Currently,thediagnosisisestablishedbydemonstratingtheabsenceofCD55orCD59onthesurfaceof
erythrocytes.Therapyissupportiveandsymptomatic,althoughoralcorticosteroidsatadoseof1to2mg/kghave
showneffectivenessatlimitingthedurationofthehemolysis[39].Hematopoieticcelltransplantationhasbeen
successfulinsomecasesinbothadultsandchildren[40,41].Eculizumabisemergingasapromisingtherapyin
adults.(See"Treatmentandprognosisofparoxysmalnocturnalhemoglobinuria",sectionon'Hematopoieticcell
transplantation'and"Treatmentandprognosisofparoxysmalnocturnalhemoglobinuria",sectionon'Eculizumab'.)
WilsondiseaseHemolyticanemiamayoccurinpatientswithWilsonsdiseaseandisoccasionallyapresenting
manifestation[42,43].PromptdiagnosisoftheunderlyingWilsondiseaseisimportantbecausetreatmentcanprevent
theprogressivehepaticandneuropsychiatricconsequences.EvaluationforWilsondiseaseshouldbeconsideredin
patientswithunexplainedhemolyticanemia,andisessentialinanypatientwithconcomitanthepaticorneurologic
symptoms.Themechanismforthehemolysishasnotbeenestablished.(See"Hemolyticanemiaduetodrugsand
toxins",sectionon'Wilsondisease'and"Wilsondisease:Clinicalmanifestations,diagnosis,andnaturalhistory".)
SUMMARY
Thebasicpathophysiologyofthehemolyticanemiasisareducederythrocytelifespan.Incompensationfora
reducedRBClifespan,thebonemarrowincreasesitsoutputoferythrocytes.Inthesevere,chronichemolytic
processesofchildhood,hypertrophyofthemarrowmayexpandthemedullaryspaces,producingbonychanges.
(See'Overview'above.)
Ahemolyticprocesscanbemeasureddirectlybydeterminingerythrocytesurvivalorindirectlyviathepresence
ofincreasedlevelsofthemetabolicproductsofhemolysis(eg,reducedhaptoglobin,orincreasedindirectbilirubin
orlactatedehydrogenase).Alternatively,ahemolyticprocessmaybeinferred,fromsignsofanincreaseinthe
erythrocyteproduction(eg,presenceofreticulocytosis).(See'Diagnosticprinciples'above.)
Thehemolyticdisordersmaybeclassifiedaccordingtowhethertheshortenederythrocytesurvivalisaresultof
anintrinsicabnormalityoftheerythrocyteoranextrinsicabnormalityactingonanormalerythrocyte(table1).
Thesetwocategoriesarenotmutuallyexclusive.(See'Classification'above.)
Hereditaryspherocytosis(HS)isafamilialhemolyticanemiaofvariableseverity,withsplenomegaly,and
sphericalerythrocytesfoundonthebloodsmear(picture5).Patientsmaypresentintheneonatalperiodwith
hyperbilirubinemiaorduringchildhoodoradulthoodwithsplenomegalyorchronicanemia.Patientsareatriskfor
acuteexacerbationsoftheanemiaduetoanaplastic,hemolytic,ormegaloblasticcrisis.Splenectomyalmost
invariablyproducesaclinicalcurebutshouldbedeferreduntilagesixyearsifpossible.(See'Hereditary
spherocytosis'above.)
Aninheriteddeficiencyofpyruvatekinase(PK)isthemostcommonoftheerythrocyteglycolyticenzyme
deficiencies.Theclinicalspectrumrangesfromamild,completelycompensatedhemolyticstatetosevere
anemia.Anemiaandhyperbilirubinemiamayoccurintheneonatalperiod.Intheolderpatient,pallor,scleral
icterus,andsplenomegalyareusualfindings.(See'Pyruvatekinasedeficiency'above.)
Glucose6phosphatedehydrogenase(G6PD)deficiencyisacommonconditionmanifestedbyacutehemolytic
episodesinducedbyinfectionorcertaindrugs(table2).Muchlesscommonly,G6PDdeficiencycancausea
chronichemolyticanemia.G6PDoccursinapproximately13percentofblackmenand2percentofblack
womenadifferentgenotypeaffectsindividualsofMediterranean,Arabic,andAsiandescent.Preventionof
hemolysisbyavoidingoxidantdrugsisofparamountimportance,soindividualsinhighriskgroupsshouldbe
testedforG6PDdeficiencypriortoadministrationofpotentoxidantdrugs.(See'Glucose6phosphate
dehydrogenasedeficiency'above.)
Autoimmunehemolyticanemia(AIHA)ischaracterizedbyautoantibodiestoredbloodcells.Itmayoccurinan
otherwisehealthyindividual(primaryAIHA)orinthesettingofanunderlyingsystemicdisordersuchasan
autoimmunedisease,malignancy,orimmunodeficiency(secondaryAIHA)(table4).Therearethreetypesof
primaryAIHA,eachwithadifferentunderlyingmechanismandapproachtotreatment(table3)(see'Autoimmune
hemolyticanemias'above):

https://www.uptodate.com/contents/overviewofhemolyticanemiasinchildren?topicKey=PEDS%2F5932&elapsedTimeMs=5&source=machineLearning

8/9

1/9/2016

Overviewofhemolyticanemiasinchildren

ThemostcommonformofprimaryAIHAiswarmreactivedisease,whichischaracterizedbyextravascular
hemolysis,mainlyinthespleen,withresultingsplenomegaly,jaundice,andanemia.(See'Warmreactive
hemolyticanemia'above.)
AsecondtypeofprimaryAIHAiscoldagglutinindisease,characterizedbyintravascularhemolysiswith
resultinghemoglobinemiaandhemoglobinuria.Darkcoloredurineismorecommonandsplenomegalyis
lesscommonthaninwarmreactivedisease.(See'Coldagglutininhemolyticanemia'above.)
AthirdtypeofprimaryAIHAisparoxysmalcoldhemoglobinuria,characterizedbyintravascularhemolysis
withhemoglobinemia,hemoglobinuria,andanemia.(See'Paroxysmalcoldhemoglobinuria'above.)
Paroxysmalnocturnalhemoglobinuria(PNH)isararechronicanemiawithprominentintravascularhemolysisthat
mayhaveitsonsetinlatechildhood.Hemolysisischaracteristicallyworseduringsleep,withmorning
hemoglobinuriausuallypresent.Thediagnosisisestablishedbyapositiveresultintheacidifiedserum(Ham
test),orthrombinorsucroselysistests.(See'Paroxysmalnocturnalhemoglobinuria'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
Topic5932Version21.0

https://www.uptodate.com/contents/overviewofhemolyticanemiasinchildren?topicKey=PEDS%2F5932&elapsedTimeMs=5&source=machineLearning

9/9