NeonatalLeukopeniaandThrombocytopenia

VandyBlack,M.D.,M.Sc.,FAAPMarch3,2016

April14,2011

ObjecHves

•  SummarizethedifferenHaldiagnosisofleukopeniaand/orthrombocytopeniainaneonate

•  DescribetheiniHalstepsintheevaluaHonofaneonatewithleukopeniaand/orthrombocytopenia

•  ReviewtreatmentopHonsforleukopeniaand/orthrombocytopeniaintheNICU

ClinicalCase1

•  OnedayoldmaleinfantadmiUedtotheNICUforhypoglycemiaandasepsisruleout

•  Bornat38weeksEGAbySVD•  Birthweight4lbs13oz•  Examshowsasmallcephalohematoma;nodysmorphicfeatures

•  PLTcount42KwithanotherwisenormalCBC

DefiniHons•  NormalWBCcount9-30Katbirth

– Mean18K

•  WhatistheANCandALC– <1000/mm3isabnormal– 6-8%ofinfantsintheNICU

•  Normalplateletcount:150-450,000/mm3– Notagedependent– 22-35%ofinfantsintheNICUhaveplts<150K

NeutropeniaAbsoluteneutrophilcount<1500/mm3

Category ANC* InfecHonrisk•  Mild 1000-1500 None•  Moderate500-1000 Minimal•  Severe <500 ModeratetoSevere

(Highestif<200)

•  RecurrentbacterialorfungalinfecHonsarethehallmarkofsymptomaHcneutropenia!

•  *ANC=WBCX%(PMNs+Bands)/100

DefiniHonofNeutropenia

Black and Maheshwari, Neoreviews 2009

HowtoApproachCytopenias

•  Normalvs.abnormal(considerseverity)

•  Malignantvs.non-malignant

•  Congenitalvs.acquired

•  IsthepaHentsymptomaHc

•  Transient,recurrent,cyclic,orpersistent

HowtoApproachCytopenias

•  Adequatevs.decreasedmarrowreserve•  DecreasedproducHonvs.increaseddestrucHon/sequestraHon

Decreasedneutrophil/plateletproducHon

•  Primary– Malignancy/leukemia/marrowinfiltraHon– AplasHcanemia– GeneHcdisorders

•  Secondary–  InfecHous– Drug-induced– NutriHonal

•  B12,folate,copper

IncreaseddestrucHon/sequestraHon

•  Immune-mediated

•  Drug-induced

•  ConsumpHonàHypersplenismvs.Vascular

•  NecroHzingenterocoliHs

•  Pseudo-neutropenia

•  Pseudo-thrombocytopenia(invitrofinding)

FetomaternalDisorders

Black and Maheshwari, Seminars in Perinatology 2009

OutpaHentNeonatalHematology•  BoneMarrowFailureSyndromes

– SevereandsymptomaHc

•  Immune-mediateddisorders– SevereandasymptomaHc– Usuallyresolvesby2monthsofage– MayhaveimplicaHonsforfuturechildren

•  Otherfetomaternaldisorders– Placentalinsufficiency

•  Othercausesusuallyresolvebeforedischarge

Bone Marrow Failure Syndromes

• GeneHcdisordersofhematopoiesisthataffectsoneormorecelllinesandmayleadtocompletemarrowfailureormalignanttransformaHon(i.e.MDS/AML)

• Mostareinherited,thoughspontaneousmutaHonsarepossible

BMFS: common clinical features • Bonemarrowfailure

•  Canbecompleteaplasiaorisolatedtoasinglecellline•  Canbeprogressive•  HypoproliferaHvecytopenias,marrowaplasia,macrocytosis(elevatedMCV)

•  AA,MDS,orleukemiamaybethefirsthematologicmanifestaHon

• CongenitalabnormaliHes(notalways)• CancerpredisposiHon

•  FamilyhistoryisessenHal(alsoconsiderotherendorgandamage)

• Maypresentinadulthood

Severe Congenital Neutropenia

• Clinicalfeatures:severe,persistentneutropeniaandrecurrentinfecHons

•  AlsoFTT,periodontaldisease• AlsoknownasKostmann’ssyndrome• GeneHcs:AD,AR,andsporadicmutaHons•  ELA-2/ELANE,HAX-1,andothers•  Treatment:SurveillanceforMDS/AML(about2%/year),oralcare,prompttreatmentforsuspectedinfecHons,G-CSF,HSCT

Cyclic Neutropenia

• ADorsporadicinheritance• Neutrophilelastasegene

•  leadingtoapoptosisofmyeloidprecursors

• Prevalence:1permillion• Reallycyclichematopoiesis• Cycles14-28days(average21days)• Neutropenialasts3-5days•  10%paHentsdeveloplife-threateninginfecHons• Noincreasedriskofmalignancies

Shwachman-Diamond Syndrome •  Clinicalfeatures:triadofneutropenia,exocrinepancreaHcinsufficiency,andskeletalabnormaliHes

•  MayalsohaveneutrophildysfuncHon•  GeneHcs:ARmutaHonsintheSBDSgene(90%ofpaHents)•  TesHng:Skeletalsurvey,evaluaHonformalabsorpHon

•  LowserumtrypsinogenandpancreaHcisoamylase(valuesareage-dependent)

•  Lowfecalelastase•  FaUypancreasonCTscan•  PancreaHcsHmulaHontesHngbypediatricGI

•  Treatment:surveillanceforMDS/AML,supporHvecare,pancreaHcenzymereplacement,ADEKvitaminsupplementaHon,HSCT

Blacketal,PediatrBloodCancer2008

Congenital AmegakaryocyBc Thrombocytopenia

• Clinicalfeatures:severethrombocytopeniaandbleeding

•  Rarecongenitalanomalies,medianageatpresentaHon7days

• GeneHcs:AR,c-MPL(TPOreceptor)•  2clinicalgroupscharacterizedbyearly(80%)orlateprogression(20%)toaplasHcanemia

•  8%ofpaHentsdevelopMDS/AML

•  TesHng:exclusionofimmune-mediatedcauses•  Treatment:transfusions,HSCT(evenifalternaHvedonorsourcesarerequired)

Thrombocytopenia Absent Radius Syndrome

• Clinicalfeatures:thesamesaysitall!!!!•  Plateletcount<50Katbirth•  Otheranomaliesmaybepresent

• GeneHcs:?1q21.1•  Therapyandoutcome

•  Plateletcountincreasesto>100Kbyoneyearofage(usually)

•  FewcasesofALL/AMLhavebeenreported•  HSCTinplatelet-refractorypaHents

TAR Syndrome

TAR vs. FA

Shimamura,BloodReviews2010

WiskoH-Aldrich Syndrome

• Clinicalfeatures:triadofthrombocytopenia,eczema,andrecurrentinfecHons

•  TandBcelldeficits,inabilitytoformanHbodies

• PayaUenHontotheMPV•  Increasedriskofleukemia/lymphoma• GeneHcs:X-linkeddisorderintheWASPgene•  Treatment:platelettransfusions,IVIG,Amicar,HSCT

Immune-mediated Disorders • Neonatalalloimmuneneutropenia/NAIT• Neonatalautoimmuneneutropenia/thrombocytopenia(i.e.maternalITP)

• Autoimmuneneutropeniaofinfancy/ITP(i.e.babyhasITP)–lesscommonintheNICU

Neonatal Alloimmune Thrombocytopenia

• Mostcommoncauseofearly,severethrombocytopenia

• MostcommoncauseofICHintermneonates•  Trueincidenceisunknown

•  Generallyquotedtobe1:1,000-1:5,000•  ScreeningisrecommendedwhenPLTs<50Katbirth(basedondatafromHPA-1aincompaHbility)

• Worsenswithsubsequentpregnancies• Plateletcountusuallystabilizeswithin2weeks

Lymphopenia

• Absolutelymphocytecount(ALC)=WBCX%(lymphocytes)/100

• Normalvaluesareagedependent•  AdultshaveameanALCof1,800/mm3•  HigherALCsininfants(mean6,700/mm3)

• Generally,lessthan1,000/mm3isabnormal•  ALC<1,000-2,000/mm3inaninfant<2monthsofageishighlyabnormalàconsiderSCID

DiagnosBc ConsideraBons

•  Severityofcytopenias• DuraHonofcytopenias•  IsthepaHentsymptomaHc?•  IsthepaHentsick?

•  EvidenceofinfecHon,NEC,orDIC•  Timing:Onset<72hoursvs.>72hours•  Evidenceofplacentalinsufficiency

•  Birthweight•  Maternalhypertension•  Apgarscores

DiagnosBc ConsideraBons

• Maternallabs•  Familyhistory• AssociatedFindings(e.g.Barthsyndrome)• Carefulphysicalexam

•  Dysmorphicfeatures,esp.radialorthumbabnormaliHes•  HepatosplenomegalyàTORCH,GSD•  Skin/hair/pigmentabnormaliHesàChediak-Higashi•  HemangiomasàKasabach-MerriUsyndrome

LaboratoryEvaluaHon•  CBCwithdifferenHal

– Noteothercelllines– Don’tforgetabouttheMCV

•  CMP•  Peripheralbloodsmear•  Ifthrombocytopenic,assessforconsumpHon

– PT,PTT,fibrinogen•  AnH-neutrophilanHbodyscreenifneutropenic

– Doesnotruleoutimmune-mediatedneutropenia

Case2

AddiHonalTests•  Imaging:skeletalsurvey,abdominalUS•  Immune-mediatedtesHngtospecializedlaboratories– UsuallyBloodCenterofWisconsinorRedCrossNeutrophillaboratory

– Maternalsamplerequired

•  Bonemarrowaspirate/biopsymaybehelpfulintheappropriatesesng

•  GenetesHngforBMFsyndromes

Treatment:Neutropenia

•  SupporHvecare/anHmicrobials•  G-CSFisthemainstayoftreatment

– StarHngdose5-10mcg/kgdailySQorIV

•  AdjuncHvetherapiesmaybeconsideredinimmune-mediatedneutropenias–  IVIG0.5-1gm/kgàsomeresponseinabout50%ofcases,butrepeatdosesareouenrequired

– VariableresultswithcorHcosteroids

WhentoStartG-CSF*

*Modified from RD Christensen In: Hematology, Immunology, and Infectious Diseases, 2nd Ed.

Treatment:Thrombocytopenia

•  PlatelettransfusionsarethemainstayoftreatmentinsymptomaHcorseverethrombocytopenia

•  ObtainaheadUStoruleoutICH•  ConsiderIVIGand/orsteroidsifthrombocytopeniaispresentatbirth

NAITTreatment

•  Treatmentisgenerallyindicatedforplateletcounts<30K(<50KifhighriskforICH)– Goal>100KincasesofICH

•  IVIG1gm/kgx2days•  +/-steroids(e.g.Methylprednisolone1mgIVevery8hoursonthedaysIVIGisgiven)– Typicaldoseis1-4mg/kg/day– ConsiderriskoffungalinfecHonsintheneonatalperiod

PlateletTransfusions

•  Thresholdsfortransfusionremaincontroversialandtosomedegreemustbeindividualizedbasedonthebleedingrisk

•  Usualdoseof10-15mls/kgofaCMV-safeproduct(pheresedorrandomdonor)

•  PLTsshouldbeleukoreduced•  IrradiaHonisindicatedforsuspectedT-celldeficiency/dysfuncHon(DiGeorge,WAS)orBW<1500gms

PlateletTransfusionsandNAIT

•  Maternalplatelets–mustbeirradiatedandplasmareducedorwashed

•  RandomdonorplateletsthatarecrossmatchcompaHbleornegaHvefortheidenHfiedanHgen(e.g.HPA-1anegaHveplatelets)

•  RandomdonorplateletswithIVIG+/-steroids(mostcommonunlessinuterodiagnosishasbeenmade)

Summary

•  LeukopeniaandthrombocytopeniaarecommonfindingsintheNICU

•  Mostcasesaremild-moderateinseverityandtransient

•  Considerimmune-mediatedcausesandBMFsyndromesincasesthataresevereand/orpersistent

Summary

•  Don’tforgetaboutthemotheràfetomaternaldisordersareanimportantconsideraHon

•  ManypotenHalconfoundersinasickneonate•  Thetwomostimportantlabsareouentheplateletcount(orANC)atbirthandmom’splateletcount(orANC)

•  Theanswerisnotalwaysimmediate

References

•  KyonoWandCoatesTD.ApracHcalapproachtoneutrophildisorders.PediatrClinNAm2002;49:929-971.

•  OhlsRKandMaheshwariA.Hematology,Immunology,andInfecHousDiseases,2ndEd.

•  BlackLVandMaheshwariA.Immune-mediated

neutropeniaintheneonate.Neoreviews2009;10:446-53.

References

•  BlackLVandMaheshwariA.DisordersoftheFetomaternalUnit:HematologicManifestaHonsintheFetusandNeonate.SeminPerinatol2009;33:12-19

•  BusselJBandSola-VisnerM.CurrentApproachestotheEvaluaHonandManagementoftheFetusandNeonatewithImmuneThrombocytopenia.SeminPerinatol2009;33:35-42.