neonatal leukopenia and thrombocytopenia · neonatal leukopenia and thrombocytopenia vandy black,...
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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– <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.
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