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