NeonatalHematopoiesisandRBCDisorders

VandyBlack,MD,MScPediatricHematology

June2,2016

Objectives

• Reviewnormalerythropoiesisinthefetusandneonateandregulationoffetalhemoglobin

• OutlinethedifferentialdiagnosisofneonatalRBCdisorderswithafocusontheclinicalandlaboratoryfindings

• Discusscommonpresentationsofintrinsicredcelldisordersinneonates

Whichofthefollowinginfantsismostlikelytobediagnosedwithaprimaryhematologicdisorder(i.e.needongoingfollow-upinmyoffice)?

A. Afull-termmalewithaHbof7.5gm/dL atbirth(MCV108)

B. AoneweekoldwithanewbornscreenthatshowsHbFAS

C. Afull-termCaucasianmalewithapeakbilirubinof21mg/dL whosemomisAB+

D. A26weekAAfemalewhosefatherhasahistoryofG6PDdeficiency

RBCDisordersintheNICU

• AnemiaisacommonfindingintheNICU• Differentialisbroad• HospitalizedpreterminfantsreceivemorePRBCtransfusionsthananyotherpatientgroup

• >80%ofELBWinfantsreceiveatleastonePRBCtransfusion

HowRBCDisordersPresent?

• AnemiaonaCBC– Maybeanexpectedorincidentalfinding

• AbnormalRBCindices• Abnormalnewbornscreens• Hyperbilirubinemia• Screeningbecauseoffamilyhistory

WhatisNormal?

Christensenetal,SeminPerinatol2009

WhatisNormal?

Christensenetal,SeminPerinatol2009

HemoglobinSwitching

HowtoApproachAnemia

• Areothercelllinesinvolved?

• WhatistheMCV?

• Whatisthereticulocytecount?

• Whatdoestheperipheralbloodsmearshow?

MicrocyticAnemia

• IronDeficiency– Ironsupplementationforpreterminfants

• Thalassemia– Beta-thalassemia lesslikelyintheneonatalperiod

• ChronicInflammation– Disordersofirontransport(e.g.TMPRSS6)

• Raredisorders– Unstablehemoglobins,sideroblasticanemia,copperdeficiency

HemoglobinGenes

Phenotype–GenotypeRelationshipinα-Thalassemia

Piel FB, Weatherall DJ. N Engl J Med 2014;371:1908-1916.

AlphaThalassemia

BetaThalassemia

MacrocyticAnemia

• Drug-induced,esp.AEDs• Down’ssyndrome• Liverdisease• Bonemarrowfailuresyndromes• Hypothyroidism(inadults)• B12orfolicaciddeficiency(rare)• Dyserythropoieticanemia(veryrare)

Diamond-Blackfan Anemia• Clinicalfeatures:macrocyticanemia,reticulocytopenia,normalbonemarrowcellularitywithapaucityoferythroidprecursors

• About50%ofpatientshavecongenitalabnormalities• Genetics:AD(sporadicorinherited)mutationsinribosomalproteins

• 9genesdescribed,manypatientshaveunknownmutations

• Testing:redcellADA(elevatedin80%ofpatients)• Treatment:steroids,chronictransfusions,HSCT• Someincreasedriskofmalignancies– AML,MDS,colon,osteosarcoma,femalegenitalcancers

FanconiAnemia• Clinicalfeatures:marrowfailure,congenitalanomalies(75%),andfamilyhistorysuggestiveofcancerpredisposition

• Pathogenesis:defectiveDNArepairleadingtochromosomalfragility

• Genetics:AR(99%;12genes)andX-linked(1%;FANCB)

• Testing:Chromosomalbreakagestudies• Increasedchromosomalbreakagefollowingexposureofpatient’slymphocytestomitomycinCordiepoxybutane(DEB)

• Ifbloodisnegative,cantestfibroblastsifyouhaveahighclinicalsuspicion

NormocyticAnemia,elevatedretic• Bloodlossvs.hemolysis• BloodlossismorecommonintheNICU

– Obstetricalcauses(e.g.placentalabruption)– Feto-maternalhemorrhage(Kleihauer-Betketestonmom)

– Twin-twintransfusion– Internalhemorrhage– Iatrogenicbloodloss

• Probablythemostcommoncauseofanemia(andtransfusion)inpreterminfants

NormocyticAnemia,elevatedretic

• Hemolysis– Intrinsic

• Membrane,Hb,andenzymedefects

– Extrinsic• Immune-mediated,esp.alloimmuneprocesses• Microangiopathiccauses(DIC,congenitalTTP)• Congenitalheartdisease• Kasabach-Merrittsyndrome• Drugorinfection-induced• VitaminEdeficiency(ofhistoricalinterestmostly)

HereditarySpherocytosis

• Mostcommoncauseofnon-immunehemolyticanemiaintheCaucasianpopulation

• CanbeduetoAD,AR,orsporadicmutations• Varyingdegreesofanemia• Consideranevaluationifapatienthasjaundiceinthefirst24hoursoflifeorearlygallstones

• Clue:elevatedMCHC(>36%)onaCBC• Increasedosmoticfragility

HS–ClinicalVariability

Gallagher, Pediatr Clin N Am 2013; 60: 1349-62

HS– morphologicvariability

Gallagher, Pediatr Clin N Am 2013; 60: 1349-62

HS– geneticvariability

Christensen et al, Pediatrics 2015; 135: 1107

HS– Diagnosis

Christensen et al, Pediatrics 2015

EvaluationofHS*

Christensen et al, Pediatrics 2015

*Family studies can also be very helpful

G6PD

• X-linkedinheritance• MostcommoninAfricanAmericansandthoseofMediterraneandecent

• Hemolysisoccursinresponsetooxidativestress– Avoidfavabeans,naphthalene,sulfadrugs– http://g6pddeficiency.org

• G6PDassaymaynotbereliableinthesettingofanacutehemolyticevent

OtherRBCEnzymeDefects

Gallagher Hematology 2015

MaternalAlloimmunization

SeminPerinatol2009

MaternalAlloimmunization*

*MinorBloodGroupAntigens:“KellKills,DuffyDies,butLewisLives”

BloodTypingBloodtype

Donorincidence

Abspresent

A 44% Anti-B

B 8% Anti-A

AB 4% NeitherAnti-AnorB

O 44% BothAnti-AandB

NormocyticAnemia,decreasedretic

• “Normal(?)”findinginpreterminfants• Primarymarrowdisorder• Acutebloodlossorhemolysis• Acuteinfectionsorinflammation

– Includescongenitalinfections(e.g.parvovirusB19)

• TORCHinfections(e.g.Rubella)• Anemiaorprematurity

AnemiaofPrematurity• RBCproductionnaturallydecreasesafterbirthasaresultofincreasedtissueoxygenationduetotheonsetofbreathingandclosureoftheductusarteriosus

• Reducedproductionoferythropoietin• Confoundedinprematureinfantsbybloodlossfromphlebotomy,reducedRBClifespan,irondepletion,andincreasedoxidativestress

• Leadstoexaggeratedphysiologicnadirs

EvaluationofHyperbilirubinemia

• FractionatethebilirubinandcheckaCBCtonarrowthedifferential

• IndirectHyperbilirubinemia• DirectHyperbilirubinemia• Consideradditionalhematologicevaluationforindirecthyperbilirubinemiarequiringphototherapy>2days,peakbilirubinlevels>20mg/dL,orhyperbilirubinemiainthefirst24hoursoflife

NeonatalHyperbilirubinemia

Christensen et al, Pediatrics 2015

NewbornScreenInterpretation

• Performedinall50statestoidentifySCD• Considerablevariationinmethodologyandimplementation

• IdentificationofHbvariants– Isthepatientsymptomatic?– IsHbApresent

• Commonpatterns(ordermatters)– SCD(FS,FSA,FSC),SCT(FAS),beta-thalmajor(fetalonly),alpha-thal(Barts)

TreatmentofRBCDisorders• PRBCtransfusions

– Goalistomaintainadequateoxygencarryingcapacity

– RemembertoirradiatebloodproductsincasesofsuspectedT-celldysfunction/deficiencyorBW<1500gms

• EPO– Willnotprovideanimmediateincreaseinoxygendelivery

– Bestusedincombinationwithiron(andothersubstratesasneeded)

EarlyEPOAdministration???• Meta-analysisofearly(startedbefore8daysofage)EPOadministrationinpreterm(<37weeks)and/orLBW(<2500g)neonates

• 23studiesenrolling2074infantsfrom18countries

• RRfor“useofoneormoreRBCtransfusions”0.80(95%CI0.75-0.86)

• RRof>stage3ROP1.71(95%CI1.15-2.54)• EarlyEPOnotrecommended

OhlssonandAher,CochraneDatabase2006,updated2012

Conclusions• AnemiaisacommonclinicalfindingintheNICUwithabroaddifferentialdiagnosis

• Mostcasesareacquired,butprimaryhematologicdisordersarelikelyunderdiagnosed

• AsystematicapproachtotheevaluationandtreatmentofRBCdisordersseemsdesirable

• ImprovedtreatmentsforneonatalRBCdisordersarerequired