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  • 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

  • NeutropeniaAbsoluteneutrophilcount

  • 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

    PrimaryMalignancy/leukemia/marrowinfiltraHonAplasHcanemiaGeneHcdisorders

    Secondary InfecHousDrug-inducedNutriHonal

    B12,folate,copper

  • IncreaseddestrucHon/sequestraHon

    Immune-mediated

    Drug-induced

    ConsumpHonHypersplenismvs.Vascular

    NecroHzingenterocoliHs

    Pseudo-neutropenia

    Pseudo-thrombocytopenia(invitrofinding)

  • FetomaternalDisorders

    Black and Maheshwari, Seminars in Perinatology 2009

  • OutpaHentNeonatalHematology BoneMarrowFailureSyndromes

    SevereandsymptomaHc Immune-mediateddisorders

    SevereandasymptomaHcUsuallyresolvesby2monthsofageMayhaveimplicaHonsforfuturechildren

    OtherfetomaternaldisordersPlacentalinsufficiency

    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,periodontaldiseaseAlsoknownasKostmannssyndromeGeneHcs:AD,AR,andsporadicmutaHons ELA-2/ELANE,HAX-1,andothers Treatment:SurveillanceforMDS/AML(about2%/year),oralcare,prompttreatmentforsuspectedinfecHons,G-CSF,HSCT

  • Cyclic Neutropenia

    ADorsporadicinheritanceNeutrophilelastasegene

    leadingtoapoptosisofmyeloidprecursorsPrevalence:1permillionReallycyclichematopoiesisCycles14-28days(average21days)Neutropenialasts3-5days 10%paHentsdeveloplife-threateninginfecHonsNoincreasedriskofmalignancies

  • 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!!!! Plateletcount100Kbyoneyearofage(usually)

    FewcasesofALL/AMLhavebeenreported HSCTinplatelet-refractorypaHents

  • TAR Syndrome

  • TAR vs. FA

    Shimamura,BloodReviews2010

  • WiskoH-Aldrich Syndrome

    Clinicalfeatures:triadofthrombocytopenia,eczema,andrecurrentinfecHons

    TandBcelldeficits,inabilitytoformanHbodiesPayaUenHontotheMPV Increasedriskofleukemia/lymphomaGeneHcs:X-linkeddisorderintheWASPgene Treatment:platelettransfusions,IVIG,Amicar,HSCT

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

    Autoimmuneneutropeniaofinfancy/ITP(i.e.babyhasITP)lesscommonintheNICU

  • Neonatal Alloimmune Thrombocytopenia

    Mostcommoncauseofearly,severethrombocytopenia

    MostcommoncauseofICHintermneonates Trueincidenceisunknown

    Generallyquotedtobe1:1,000-1:5,000 ScreeningisrecommendedwhenPLTs

  • Lymphopenia

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

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

    Generally,lessthan1,000/mm3isabnormal ALC

  • DiagnosBc ConsideraBons

    SeverityofcytopeniasDuraHonofcytopenias IsthepaHentsymptomaHc? IsthepaHentsick?

    EvidenceofinfecHon,NEC,orDIC Timing:Onset72hours Evidenceofplacentalinsufficiency

    Birthweight Maternalhypertension Apgarscores

  • DiagnosBc ConsideraBons

    Maternallabs FamilyhistoryAssociatedFindings(e.g.Barthsyndrome)Carefulphysicalexam

    Dysmorphicfeatures,esp.radialorthumbabnormaliHes HepatosplenomegalyTORCH,GSD Skin/hair/pigmentabnormaliHesChediak-Higashi HemangiomasKasabach-MerriUsyndrome

  • LaboratoryEvaluaHon CBCwithdifferenHal

    NoteothercelllinesDontforgetabouttheMCV

    CMP Peripheralbloodsmear Ifthrombocytopenic,assessforconsumpHon

    PT,PTT,fibrinogen AnH-neutrophilanHbodyscreenifneutropenic

    Doesnotruleoutimmune-mediatedneutropenia

  • Case2

  • AddiHonalTests Imaging:skeletalsurvey,abdominalUS Immune-mediatedtesHngtospecializedlaboratoriesUsuallyBloodCenterofWisconsinorRedCrossNeutrophillaboratory

    Maternalsamplerequired Bonemarrowaspirate/biopsymaybehelpfulintheappropriatesesng

    GenetesHngforBMFsyndromes

  • Treatment:Neutropenia

    SupporHvecare/anHmicrobials G-CSFisthemainstayoftreatment

    StarHngdose5-10mcg/kgdailySQorIV AdjuncHvetherapiesmaybeconsideredinimmune-mediatedneutropenias IVIG0.5-1gm/kgsomeresponseinabout50%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

  • PlateletTransfusions

    Thresholdsfortransfusionremaincontroversialandtosomedegreemustbeindividualizedbasedonthebleedingrisk

    Usualdoseof10-15mls/kgofaCMV-safeproduct(pheresedorrandomdonor)

    PLTsshouldbeleukoreduced IrradiaHonisindicatedforsuspectedT-celldeficiency/dysfuncHon(DiGeorge,WAS)orBW

  • PlateletTransfusionsandNAIT

    Maternalplateletsmustbeirradiatedandplasmareducedorwashed

    RandomdonorplateletsthatarecrossmatchcompaHbleornegaHvefortheidenHfiedanHgen(e.g.HPA-1anegaHveplatelets)

    RandomdonorplateletswithIVIG+/-steroids(mostcommonunlessinuterodiagnosishasbeenmade)

  • Summary

    LeukopeniaandthrombocytopeniaarecommonfindingsintheNICU

    Mostcasesaremild-moderateinseverityandtransient

    Considerimmune-mediatedcausesandBMFsyndromesincasesthataresevereand/orpersistent

  • Summary

    DontforgetaboutthemotherfetomaternaldisordersareanimportantconsideraHon

    ManypotenHalconfoundersinasickneonate Thetwomostimportantlabsareouentheplateletcount(orANC)atbirthandmomsplateletcount(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.