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第20部分:儿童中的抗凝治疗

发布时间:2013-11-27 08:35:32  

AntithromboticTherapyinChildren*

TheSeventhACCPConferenceonAntithromboticandThrombolyticTherapy

PaulMonagle,MBBS,MSc,MD,FCCP;

AnthonyChan,MBBS;PattiMassicotte,MD,MSc;ElizabethChalmers,MDChB,MD;andAlanD.Michelson,MD

Thisarticleaboutantithrombotictherapyinchildrenispartofthe7thAmericanCollegeofChestPhysi-ciansConferenceonAntithromboticandThrombo-lyticTherapy:Evidence-BasedGuidelines.Grade1recommendationsarestrongandindicatethatthebenefitsdo,ordonot,outweightherisks,burden,andcosts.Grade2suggeststhatindividualpatients’valuesmayleadtodifferentchoices(forafullunderstandingofthegradingseeGuyattetal,CHEST2004;126:179S–187S).Amongthekeyrec-ommendationsinthisarticlearethefollowing.Inneonateswithvenousthromboembolism(VTE),wesuggesttreatmentwitheitherunfractionatedhepa-rinorlow-molecular-weightheparin(LMWH),orradiographicmonitoringandanticoagulationther-apyifextensionoccurs(Grade2C).WesuggestthatcliniciansnotusethrombolytictherapyfortreatingVTEinneonates,unlessthereismajorvesselocclu-sionthatiscausingthecriticalcompromiseoforgansorlimbs(Grade2C).Forchildren(ie,>2monthsofage)withaninitialVTE,werecommendtreatmentwithIVheparinorLMWH(Grade1C?).Wesuggestcontinuinganticoagulanttherapyforidiopathicthromboembolicevents(TEs)foratleast6monthsusingvitaminKantagonists(targetinternationalnormalizedratio[INR],2.5;INRrange,2.0to3.0)oralternativelyLMWH(Grade2C).WesuggestthatcliniciansnotusethrombolytictherapyroutinelyforVTEinchildren(Grade2C).Forneonatesandchil-drenrequiringcardiaccatheterization(CC)viaanartery,werecommendIVheparinprophylaxis(Grade1A).Wesuggesttheuseofheparindosesof100to150U/kgasabolusandthatfurtherdosesmayberequiredinprolongedprocedures(bothGrade2B).ForprophylaxisforCC,werecommendagainstaspirintherapy(Grade1B).Forneonatesandchil-drenwithperipheralarterialcathetersinsitu,werecommendtheadministrationoflow-doseheparinthroughacatheter,preferablybycontinuousinfu-siontoprolongthecatheterpatency(Grade1A).Forchildrenwithaperipheralarterialcatheter-relatedTE,wesuggesttheimmediateremovalofthecath-eter(Grade2C).Forpreventionofaorticthrombosissecondarytotheuseofumbilicalarterycathetersinneonates,wesuggestlow-doseheparininfusion(1to5U/h)(Grade2A).InchildrenwithKawasakidis-ease,werecommendtherapywithaspirininhigh

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dosesinitially(80to100mg/kg/dduringtheacutephase,forupto14days)andtheninlowerdoses(3to5mg/kg/dfor>7weeks)[Grade1C?],aswellastherapywithIVgammaglobulinwithin10daysoftheonsetofsymptoms(Grade1A).

(CHEST2004;126:645S–687S)

Keyembolism

words:antithrombotic;child;heparin;pediatric;thrombo-Abbreviations:emicADP?ATtion;?antithrombin;stroke;aPTT?activatedadenosinediphosphate;partialthromboplastinAIS?arterialtime;isch-CSVTCHD?congenitalBT?Blalock-Taussig;heartdisease;CICC??cardiaccatheteriza-DVTFXabocytopenia;???factordeepcerebralXa;venoussinovenousthrombosis;CVL?confidencecentralvenousinterval;line;GP?glycoprotein;thrombosis;HITFFP??heparin-inducedfresh-frozenplasma;throm-normalizedweightratio;ICHIVC?intracranial?inferiorvenahemorrhage;cava;INR?internationalproteinheparin;PSC;PE?MRV?magneticresonanceLMWHvenography;?low-molecular-PC?randomized?proteinS;pulmonaryPTS?post-thromboticembolism;PICUsyndrome;?pediatricRCTICU;?thrombosis;controlledTESK?streptokinase;trial;RR?relativeSVTrisk;RVT?renalveinTPN?UFH?thromboembolicvein?totalunfractionatedparenteralevent;nutrition;tPA?tissue?sinovenousplasminogenthrombosis;activator;heparin;UKUAC??urokinase;umbilicalUVCarterial?umbilicalcatheter;embolism

catheter;VKA?vitaminKantagonist;VTE?venousthrombo-antithromboticThepreventionandtreatmentofthromboemboliccom-plicationsinspecificpediatricpopulationsrequires

therapy.Recommendationsforantithrom-botictherapyinpediatricpatientshavebeenextrapolatedfromrecommendationsforadults,becausethromboem-bolicevents(TEs)inpediatricpatientswererareenoughtohindertestingofspecifictherapeuticmodalities,yetwerecommonenoughtopresentsignificantmanagementdilemmasthatrequiredtherapeuticintervention.1,2

Advancesintertiarycarepediatricshaveparadoxicallyresultedinrapidlyincreasingnumbersofchildrenrequir-ingantithrombotictherapy.Interventiontrialsarenowbothfeasibleandurgentlyneededtoprovidevalidatedguidelinesforantithrombotictherapyinneonatesandchildren.Sincethefirstpublicationofthisarticleinthe1995CHESTantithromboticsupplement,3tionalrandomizedcontrolledinterventiontrials?10assessingmultina-specificaspectsofanticoagulanttherapyinchildrenhavebeeninitiated,andmostofthesehavefailedtoenrollanadequatenumberofpatientstoanswertheprimarystudyquestion.4–6Themajorityofthearticlespublishedintheavailableliteraturetosupporttherecommendationsinthispublicationareuncontrolledstudies,casereports,orinvitroexperiments.Unfortunately,therehasnotbeenadramaticimprovementinthequalityofevidencesincethefirstpublicationofthisarticle.

Thisarticleisdividedintothreeparts.Thefirstsection

Reproductionsionpermissions@chestnet.org).

fromtheofAmericanthisarticleCollegeisprohibitedofChestwithoutPhysicianswrittenpermis-(e-mail:CorrespondenceDivisionDepartmentofto:PaulMonagle,MBBS,MSc,MD,FCCP,Children’sAustralia3052;Hospital,ofLaboratoryPaediatrics,Services,RoyalChildren’sHospital,e-mail:FlemingtonUniversityofMelbourne,c/oRoyalpaul.monagle@wch.org.au

Rd,Parkville,Melbourne,VIC,CHEST/126/3/SEPTEMBER,2004SUPPLEMENT

645S

detailstheevidenceshowingthattheinteractionofanti-thromboticagentswiththehemostaticsystemofyoungpatientsdiffersfromthatofadultpatients.Thissectiondescribesthemechanismsofaction,therapeuticranges,doseregimes,monitoringrequirements,factorsinfluenc-ingdose-responserelationships,andsideeffectsofanti-thrombotic,antiplatelet,andthrombolyticagentsinneo-natesandchildren.Thesecondsectiondiscussesbackgroundinformationregardingthebiologicalrationalerelatedtospecificantithromboticagents,andevidenceregardingappropriateadministrationandsideeffects,anditreviewsevidenceregardingthrombophilicmarkers.Thefinalsectionprovidestheevidenceandrecommendationsforantithrombotictherapyinpediatricpatients.

Throughoutthisarticle,thetermpediatricpatientsisusedtorefertoallneonatesandchildren(ie,frombirthto16yearsofage).Thetermneonatesreferstoinfantsfrombirthto28daysofagecorrectedforgestationalage.Thetermchildrenreferstopatients28daysto16yearsofage.ComprehensiveliteraturesearcheswereperformedaspertheAmericanCollegeofChestPhysiciansguidelinesforthispublication(Table1),andrecommendationswerebasedontheAmericanCollegeofChestPhysiciansgradesofrecommendation.

AntithromboticTherapyinPediatric

Patients

Thereareamultitudeofimportantvariablesthatmaketheuseofantithromboticdrugsinpediatricpatientsdifferentfromtheuseofthesamedrugsinadults.First,theepidemiologyofTEsinpediatricpatientsisvastlydifferentfromthatseeninadults.Second,thehemostaticsystemisadynamicevolvingentity,whichnotonlylikelyaffectsthefrequencyandnaturalhistoryofTEsinchil-dren,butalsotheresponsetotherapeuticagents.Third,thedistribution,binding,andclearanceofantithromboticdrugsareage-dependent.Fourth,thefrequencyandtypeofintercurrentillnessesandconcurrentmedicationsvarieswithage.Fifth,theneedforgeneralanesthesiatoperformmanydiagnosticstudiesinpediatricpatientsimpactsontheabilitytoconfirmandmonitorTEs,andhencetheconfidenceintherapeuticdecisions.Sixth,vascularaccess,whileamajorcauseofTEsinpediatricpatients,alsopresentssignificantdifficultiesintreatingTEs.Fre-quently,thechoiceofantithromboticagentisdecidedbythepracticalabilitytodeliverthedrug.Often,theonlyvascularaccessavailableisusedfordrugdelivery,andsotheaccuratemonitoringofbloodanticoagulantlevelsisnotpossible.Seventh,therearenospecificpediatricformulationsofantithromboticdrugs,makingaccurate,reproducible,weight-adjusteddosingdifficult.ThisisespeciallythecaseforvitaminKantagonists(VKAs)[nosuspension/liquidpreparation]andlow-molecular-weightheparin(LMWH)[availablemostreadilyinpredosedsyringes].Eighth,dietarydifferencesmaketheuseoforalVKAsparticularlydifficult,especiallyinneonatesgiventhatbreastmilkandinfantformulashavevastlydifferentvitaminKlevels.Finally,complianceissuesarevastlydifferentin,forexample,smallinfantswhocannotunder-646S

standtheneedfortherapy,adolescentswhointellectuallycomprehendbutemotionallyareunabletocooperate,andchildrenindysfunctionalfamilieswhoexperiencetheeffectsofinadequateparenting.Thesocial,ethical,andlegalimplicationsoftheseissuesfrequentlyinterferewiththeabilitytoprovidethe“best”treatmentforindividualneonatesandchildren,andcannotbeunderestimated.Whilenumerousstudieshavedefinedappropriatediag-nosticstrategiesinadultswitharangeofTEs,theoptimaldiagnosticstrategiesinchildrenwhohaveexperiencedTEsremaincontroversialand,inmanycases,unproven.Inparticular,therearephysiologic,pathologic,andpracticalreasonswhythesimpleextrapolationofadultdiagnosticstrategiesisinsufficient.AfulldiscussionofoptimaldiagnosticstrategiesforTEsinneonatesandchildrenisbeyondthescopeofthisarticle.Readerscanconsultseveralrecentstudiesandreviews.6–29

Insummary,themanagementofTEsinchildrendifferssignificantlyfromthemanagementofTEsinadults.Whiletherearenoformalstudiestosupportarecommendation,theauthorssuggestthat,wherepossible,pediatrichema-tologistswithexperienceintreatingTEsmanagepediatricpatientswithTEs.Whenthisisnotpossible,acombina-tionofaneonatologist/pediatricianandadulthematologistsupportedbyconsultationwithanexperiencedpediatrichematologist(eg,the1–800-NOCLOTSserviceorothernationalreferralcenters)providesareasonablecompro-mise.

HeparinandLMWHinNeonatesandChildren

Heparin

Unfractionatedheparin(UFH)[alsocalledstandardheparin]remainsacommonlyusedanticoagulantinpedi-atricpatients.Arecentreport30hassuggestedthatinatertiarypediatrichospital,approximately15%ofinpatientsareexposedtoUFHeachday.

Mechanismofaction

Theanticoagulantactivitiesofheparin,whichareme-diatedbythecatalysisofantithrombin(AT),canbeimpairedinthepresenceofdecreasedplasmalevelsofAT.PlasmaconcentrationsofATarephysiologicallylowatbirth(approximately0.50U/mL)anddonotincreasetoadultvaluesuntil3monthsofage.31–33SickprematureneonatesfrequentlyhaveplasmalevelsofATof?0.30U/mL.33,34FetalreferencerangesarenowavailableandshowthatATlevelsrangefrom0.20to0.37U/mLatgestationalagesof19to38weeks.35

HeparinexertsantithromboticactivitybycatalyzingtheabilityofATtoinactivatespecificcoagulationenzymes,inparticularthrombin.36Thecapacityofplasmasfromneo-natestogeneratethrombinisbothdelayedanddecreasedcomparedtothatinadults,38,39anditissimilartoplasmafromadultsreceivingtherapeuticamountsofheparin.38Followinginfancy,thecapacityofplasmatogeneratethrombinincreasesbutremainsapproximately25%lessthanthatforadultsthroughoutchildhood.40Bothanincreasedsensitivityandaresistancetotheanticoagulant

SeventhACCPConferenceonAntithromboticandThrombolyticTherapy

Table1—QuestionDefinitionandEligibilityCriteriaforATinChildren

Section1.1

PopulationNeonates(premandtermupto28dcorrectedforage)Children(day28to16yr)

ConditionDVT(CVLandnon-CVL-related),PEDVT(CVLandnon-CVL-related),PEUnilateralorbilateralRVT(withorwithoutIVCextension)CVAD

InterventionorExposureAnticoagulation

(heparin/VKAs,orLMWH)Anticoagulation

(heparin/VKAs,orLMWH)Thrombolysisvs

anticoagulation,andanticoagulationvsnotreatmentLocalheparin(1–2U/mLinfusion),heparinlock,intermittentlocalthrombolysis,

systemicheparinorLMWHprophylaxisHeparinorLMWHvsaspirinprophylaxis,aspirinprophylaxisvsnotreatmentHeparinorLMWHprophylaxis

OutcomeMortality,PE,

paradoxicalstroke,postphlebiticsyndrome,recurrenceMortality,PE,

paradoxicalstroke,postphlebiticsyndrome,recurrenceMortality,renalfailure,

hypertension,extension

Patency,sepsis,DVT,PE,intracranialhemorrhage

MethodologyRCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)

ExclusionCriteriaThrombectomyandthrombolysis

1.2

Thrombectomyandthrombolysis

1.3

1.4

Neonates(premandtermupto28dcorrectedforage)

Neonates(premandtermupto28dcorrectedforage),

children(day28to16yr)Neonates(premandtermupto28dcorrectedforage),

children(day28to16yr)Neonates(premandtermupto28dcorrectedforage)Children(day28to16yr)

1.5BTshunt

Intracardiacthrombosis,mortality,tissueloss,intracranialhemorrhageIntracardiacthrombosis,mortality,tissueloss,intracranial,hemorrhageIntracardiacthrombosis,mortality,tissueloss,intracranialhemorrhage,ischemicstroke,FontansurgeryIntracardiacthrombosis,

mortality,Fontantakedown,strokePatency,mortality,PEs,ischemicstrokeMortality,thrombosis,ischemicstrokeMortalityvalvereplacement,

thrombosis,strokeMortality,valvereplacement,

thrombosis,stroke

RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)

1.6

Stage1NorwoodProcedure

1.7GlennorBCPS

HeparinorLMWHprophylaxis

1.8

Children(day28to16yr)Children(day28to16yr)Children(day28to16yr)Children(day28to16yr)Children(day28to16yr)

Fontansurgery

Heparin/LMWHandVKAs,aspirin,noprimaryprophylaxisHeparin,LMWH,oraspirinVKAsoraspirin

1.9Endovascularstents

1.10

Dilated

cardiomyopathyBiological

prostheticheartvalvesMechanical

prostheticheartvalves

1.11VKAsoraspirin

1.12

1.13

Children(day28to16years)

Surgery

Notherapy,

antiplateletagents,heparin/vitaminKantagonists,

antiplateletagents,andVKAs

Heparin,LMWHprophylaxis

RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)

DVT

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Table1—Continued

Section1.14

PopulationNeonates(premandtermupto28dcorrectedforage),

children(day28to16yr)Neonates(premandtermupto28dcorrectedforage),

children(day28to16yr)Neonates(premandtermupto28dcorrectedforage),

children(day28to16yr)Neonates(premandtermupto28dcorrectedforage)

Neonates(premandtermupto28dcorrectedforage)Neonates(premandtermupto28dcorrectedforage)Children(day28to16yr)

CC

Condition

InterventionorExposureHeparinprophylaxis

OutcomeFemoralarterythrombosis

MethodologyRCT

observational(cohortcaseseries)

ExclusionCriteria

1.15

Femoralarterythrombosis

Thrombolysis,anticoagulation(heparin/VKAs,orLMWH),

thrombectomyThrombolysisvsthrombectomy,thrombolysisorthrombectomy,anticoagulationvsnotherapy

Highposition(?T10)vslowposition(L3–L5)Heparinprophylaxisvsnoprophylaxis,thrombolysis,anticoagulationThrombolysisoranticoagulation

Claudication,legshortening,limbloss

RCT

observational(cohortcaseseries)

1.16

Peripheralarterialthrombosis

Tissueloss

RCT

observational(cohortcaseseries)

1.17UAC

Aorticthrombosis,NEC,intracranialhemorrhagePatencyaorticthrombosis,intracranial

hemorrhage,NEC,mortality

Mortality,limbloss,renalimpairment,hypertension,NEC,intracranialhemorrhage

Coronaryaneurysms,myocardial

infarction,mortalityMyocardialinfarction,mortality

1.18

Aorticthrombosis(UAC-related)

RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)RCT

observational(cohortcaseseries)

1.19

Aorticthrombosis(spontaneous)

1.20Kawasakidisease

Aspirin,IVIG,aspirinandIVIG,notreatmentVKAs,aspirin

1.21

Children(day28to16yr)

KawasakidiseasewithcoronaryaneurysmsSVT

1.22

1.23

Neonates(premandtermupto28dcorrectedforage)

Children(day28to16yr)

Heparin,LMWH,orVKAs,notreatment

Mortality,functionalstatus,intracranialhemorrhageMortality,functionalstatus,intracranialhemorrhageMortality,functionalstatus,intracranialhemorrhageMortality,functionalstatus,intracranialhemorrhageMortality,vision,neurologicoutcome,thrombosis

SVT

Heparin,LMWH,orVKAs,notreatment

1.24

1.25

Neonates(premandtermupto28dcorrectedforage)

Children(day28to16yr)

AIS

HeparinorLMWHvsaspirin,notreatmentHeparinorLMWHvsaspirin,notreatmentProteinC

replacement,VKAs,orLMWH

AIS

1.26

Neonates(premandtermupto28dcorrectedforage)

Purpurafulminans

*MRA?magneticresonancearteriography;CVAD?centralvenousaccessdevice;NEC?necrotizingenterocolitis;prem?premature;BCPS?bilateralcavopulmonaryshunt.648S

SeventhACCPConferenceonAntithromboticandThrombolyticTherapy

activitiesofUFHhavebeenreportedinvitroinplasmafromneonates.38,40IncreasedsensitivitytoUFHisob-servedinsystemsbasedonassaysthataredependentonthrombingeneration(eg,activatedpartialthromboplastintime[aPTT]).41Onestudy42oftheinvitroeffectsofUFH(0.25U/mL)onneonates,children,andadultsfoundthatthrombingenerationwasdelayedandreducedinchildrencomparedtothatinadults,andwasvirtuallyabsentinneonates.ResistancetoUFHhasbeenobserved41,43,44insystemsbasedonassaysthatmeasuretheinhibitionofexogenouslyaddedfactorXa(FXa)orthrombinandthataredependentonplasmaconcentrationsofAT.

TheparadoxofUFHsensitivityandresistanceinplasmafromneonatesreflectstheratioofATtoprothrom-binintheassaysystem.41TheinvivoantithromboticeffectsofUFHinnewbornpigletsshowthatdecreasedconcentrationsofATlimittheantithromboticeffectsofUFH.45ThisresistancetoUFHcanbeovercomebyincreasingeitherthedoseofUFHortheATconcentra-tion.45

Therapeuticrange

TherecommendedtherapeuticrangeforthetreatmentofvenousTEsinadultsisanaPTTthatreflectsaheparinlevelbyprotaminetitrationof0.2to0.4U/mLorananti-FXalevelof0.35to0.7U/mL.46TheaPTTtherapeu-ticrangesareuniversallycalculatedusingadultplasma,andwhetherextrapolationofthesetopediatricpatientsisvalidisunknown.BaselineaPTTsinpediatricpatients,especiallyneonates,areoftenincreasedcomparedtothoseinadults,andsothetherapeuticrangesrepresentareducedrelativeincrementinaPTTvaluesinpediatricpatientsreceivingheparintherapycomparedtothoseinadults.Intheabsenceoffurtherinformation,theextrap-olationoftheadulttherapeuticrangesremainsnecessary.Inpediatricpatients,aPTTvaluescorrectlypredictther-apeuticheparinconcentrationsapproximately70%ofthetime.47

Doses

ThedosesofheparinrequiredinpediatricpatientstoachieveadulttherapeuticaPTTvalueshavebeenassessedusingaweight-basednomogram(oneprospectivecohortstudy).47Bolusdosesof75to100U/kgresultintherapeu-ticaPTTvaluesin90%ofchildren.Maintenanceheparindosesareage-dependent,withinfants(upto2monthsofage,correctedforgestationalage)havingthehighestrequirements(averagedose,28U/kg/h),andchildren?1yearofagehavinglowerrequirements(averagedose,20U/kg/h).Thedosesofheparinrequiredforolderchildrenaresimilartotheweight-adjustedrequirementsinadults(ie,18U/kg/h).48

Pharmacokinetics

StudiesofUFHinnewbornsarelimitedbutshowthattheclearanceisfasterthanthatforolderchildrenduetoalargervolumeofdistribution,49,50andthatthedoseofUFHrequiredtoachieveatherapeuticaPTTisalso

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increasedcomparedtothatinolderchildren.47Pharma-cokineticstudiesinpigletsalsoshowthattheclearanceofUFHisfasterthanforthatadultpigsduetoalargervolumeofdistribution.45Heparinproteinbindinginnew-bornsalsomaybedifferentfromthatinolderchildrenandadults,althoughthisremainstobeproven.

Monitoring

TheappropriatedosageadjustmentofIVheparinther-apycanbeproblematic.48,51Heparindosingnomogramshavebeenvalidatedinchildren(Table2).47

Adverseeffects

Onecohortstudy47reportedbleedingin1.5%(95%confidenceinterval[CI],0.0to8.3%)ofchildrentreatedfordeep-veinthrombosis(DVT)/pulmonaryembolism(PE).However,manychildrenweretreatedwithsubop-timalamountsofheparin(comparedtothetargetaPTT)inthisstudy,47andfurtherstudiesarerequiredtodeter-minethetruefrequencyofheparin-inducedbleedinginchildren.Thereareonlythreecasereports52–54ofpediatricheparin-inducedosteoporosis,andintwoofthempatientsreceivedconcurrentsteroidtherapy.Thethirdreceivedhigh-doseIVheparintherapyforaprolongedperiod.55However,giventheconvincingrelationshipbetweenhep-arinandosteoporosisinadults,thelong-termuseofheparininchildrenshouldbeavoidedwhenotheralter-nativeanticoagulantagentsareavailable.Therehavebeenanumberofcasereports56–60ofpediatricheparin-inducedthrombocytopenia(HIT)intheliterature,andthepatientsdescribedinthosecasereportsrangeinagefrom3monthsto15years.Heparinexposureinthesecasesrangedfromlow-doseexposureduringheparinflushesusedinmain-tainingthepatencyofvenousaccessdevices,tosuprath-erapeuticdosesgivenduringcardiopulmonarybypassandhemodialysis.Somestudies30,61havesuggestedthatthefrequencyofHITmaybeincreasedinchildreninthepediatricICU(PICU)[2.3%]comparedtochildreninanon-PICUsetting.AhighindexofsuspicionisrequiredtodiagnoseHITinchildren,asmanypatientsintheneonatalICU/PICUwhoareexposedtoheparinhavemultiplepotentialreasonsforthrombocytopeniaand/orthrombo-sis.Danaparoidsodium(Orgaran;OrganonInc;Roseland,NJ),hirudin,andargatrobanarealternativestoheparininthetreatmentofchildrenwithHIT.56,57,59,62,63

Treatmentofheparin-inducedbleeding

Asinadults,ifanticoagulationwithheparinneedstobediscontinuedforclinicalreasons,theterminationoftheheparininfusionwillusuallysufficebecauseoftherapidclearanceofheparin.Ifanimmediateeffectisrequired,IVprotaminesulfaterapidlyneutralizesheparinactivitybyvirtueofitspositivecharge.Thedoseofprotaminesulfaterequiredtoneutralizeheparinisbasedontheamountofheparinreceivedintheprevious2h(Table3).Protaminesulfatecanbeadministeredinaconcentrationof10mg/mLataratenottoexceed5mg/min.Patientswithknownhypersensitivityreactionstofish,andthosewho

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Table2—ProtocolforSystemicHeparinAdministrationandAdjustmentforPediatricPatients*

StageIII

Description

Loadingdose

InitialmaintenancedoseInfants?1yrChildren?1yrAdjustment?

aPTT,s

Bolus,U/kg75IVover10min

28/h20/h5000000

Hold,min

RateChange,%

RepeataPTT

III

?5050–5960–8586–9596–120?12000003060?10%?10%0?10%?10%?15%4h4h

Nextday4h4h4h

IV

V

ObtainbloodforaPTTcheck4hafterheparinloadingdoseand4haftereverychangeininfusionrate

WhenaPTTvaluesareintherapeuticrange,

performdailyCBCandaPTTmeasurement

*ReproducedwithpermissionofMichelsonetal.3

?HeparinadjustedtomaintainaPTTat60to85s,assumingthatthisreflectsananti-FXalevelof0.35to0.70.

havereceivedprotamine-containinginsulinorpreviousprotaminetherapymaybeatriskofhypersensitivityreactionstoprotaminesulfate.LMWH

LMWHshaverapidlybecometheanticoagulantagentsofchoiceinmanypediatricpatients,bothforprimaryprophylaxisandthetreatmentofTE,despitetheirun-provedefficacyinmanyofthesesituations.ThepotentialadvantagesofLMWHforpediatricpatientsincludetheneedforminimalmonitoring(importantinpediatricpatientswithpoorornonexistentvenousaccess),thelackofinterferencebyotherdrugsordietsuchasexistsforVKAs,thereducedriskofHIT,andtheprobablereducedriskofosteoporosiswithlong-termusecomparedtothatwiththeuseofheparin.However,thepredictabilityoftheanticoagulanteffectwithweight-adjusteddosesappearstobereducedcomparedtothatinadults,presumablyduetoalteredplasmabinding.3,36

therapeuticLMWHsisananti-FXalevelof0.50to1.0U/mLinasampletaken4to6hfollowingasubcutaneousinjection.Theclinicalsignificanceoftheinvitrodatadescribedpreviouslyhasnotbeenestablished.

Doses

ThedosesofLMWHrequiredinpediatricpatientstoachieveadulttherapeuticanti-FXalevelshavebeenas-sessedforenoxaparin,reviparin,dalteparin,andtinzaparin(Table4).64–66,69Ingeneral,peakanti-FXalevelsoccur2to6hfollowingasubcutaneousLMWHinjection.Infantswhoarelessthanapproximately2to3monthsofageorweight?5kghaveincreasedrequirementsperkilogram,whichlikelyisduetoalargervolumeofdistribution.AlternativeexplanationsfortheincreasedrequirementofLMWHperbodyweightinyoungchildrenincludealteredheparinpharmacokinetics69and/oradecreasedexpressionoftheanticoagulantactivityofheparininchildrendueto

Mechanismofaction

Atsimilaranti-FXaconcentrations,UFHinhibitsfree-thrombingenerationtoagreaterdegreethandoesLMWHinneonates,children,andadults.Invitro,throm-bingenerationissimilarinadultsandchildrenatthesameconcentrationofLMWH.However,ataLMWHconcen-trationof0.25U/mLthrombingenerationwasdelayedandreducedbyapproximatelyhalfinnewbornscomparedtoadults.Thesedifferenceswerematchedbyreductionsintheratesofprothrombinconsumption.42

Table3—ReversalofHeparinTherapy*

Heparin

Timesincelastdose,min?3030–6060–120?120

MaximumdoseInfusionrate

ProtamineDose

1.0mg/100Uheparinreceived

0.5–0.75mg/100Uheparinreceived0.375–0.5mg/100Uheparinreceived0.25–0.375mg/100Uheparinreceived50mg

10mg/mL,solutionshouldnotexceed5mg/min

Therapeuticrange

TherapeuticdosesofLMWHareextrapolatedfromadultsandarebasedonanti-FXalevels.Theguidelinefor

650S

*Hypersensitivityreactionstoprotaminesulfatemayoccurinpa-tientswithknownhypersensitivityreactionstofish,orinthosepreviouslyexposedtoprotaminetherapyorprotamine-containinginsulintherapy.

SeventhACCPConferenceonAntithromboticandThrombolyticTherapy

Table4—DrugDoses

InitialInitialTreatmentProphylacticDrug

Dose

Dose

Reviparin

Bodyweight-dependentdose,U/kgq12h?5kg15050?5kg10030Enoxaparin

Age-dependentdose,mg/kgq12h?2mo1.50.75?2mo1.00.5Dalteparin

All-agepediatricdose,129?43

92?52

U/kgq24hTinzaparin

Age-dependentdose,U/kg0–2mo2752–12mo2501–5yr2405–10yr20010–16yr

275

decreasedplasmaconcentrationsofAT.IVdosinghasbeenreportedinoneneonate,andtheadministrationofenoxaparin,1mg/kgq8h,wasrequiredtomaintainther-apeuticanti-FXalevels.67

Adverseevents

Althoughtheriskofmajorbleedingisnotpreciselyknowninneonates,therearestudiesreportingtheriskofbleedinginneonatesaspartoflargerpatientpopulations.Onepilotstudy69reportednobleedingdocumentedinseveninfantswhowere?2monthsofage(0%;95%CI,0to47%).Inalargerseries,684of37infantshadmajorbleeding(10.8%;95%CI,3to25.4%).ThelocationofbleedingwaslocalatthesiteofsubcutaneouscathetersintwonewbornswithlittlesubcutaneoustissueandwasinpreexistingabnormalitiesintheCNSinafurthertwonewborns.Subcutaneouscathetersshouldbeusedwithcautioninnewbornswithlittlesubcutaneoustissue.Inchildreninasingle-institutioncohortstudy68of146coursesoftherapeuticenoxaparin,majorbleedingoc-curredin4.8%ofpatients(95%CI,2to9.6%).Inarandomizedtrial(37patients)ofreviparin,majorbleedingoccurredin8.1%ofpatients(95%CI,1.7to21.9%).6Therearenodataonthefrequencyofosteoporosis,HIT,orotherhypersensitivityreactionssecondarytoLMWHuseinchildren.

TreatmentofLMWH-inducedbleeding

Equimolarconcentrationsofprotaminesulfateneutral-izetheanti-factorIIaactivitybutresultinonlypartialneutralizationoftheanti-FXaactivity.70However,inanimalmodels,bleedingiscompletelyreversedbyprota-minesulfate.71–74Thedoseofprotaminesulfateisdepen-dentonthedoseofLMWHusedatthetimeofadminis-www.chestjournal.org

tration.RepeatdosesofprotaminemayberequiredaftersubcutaneousLMWH.Protocolsforreversalhavebeenpublished.71

VKAsinneonatesandchildren

VKAsfunctionasanticoagulantsbyreducingthefunc-tionalplasmaconcentrationofvitamin-Kdependentfac-tors(ie,factorsII,VII,IX,andX).ThevitaminK-dependentfactorsaredecreasedphysiologicallyinnewbornstolevelsthatarefrequentlyachievedinadultsreceivingtherapeuticamountsofVKAswithtargetINRsof2to3.VKAsareproblematicinnewbornsforseveralotherreasons.First,infantformulaissupplementedwithvitaminKtopreventhemorrhagicdiseaseofthenewborn,whichmakesformula-fedinfantsresistanttoVKAs.Incontrast,breastmilkhaslowconcentrationsofvitaminK,makingbreast-fedinfantsverysensitivetoVKAs.75,76Thelattercanbecompensatedforbyfeedingbreast-fedneonates1to2ozformulaeachday.Second,VKAsareavailableonlyintabletform.Althoughthetabletscanbedissolvedinwaterforadministrationtonewborns,therearenostabilitydataorcriticalassessmentsofthispractice.Third,VKAsrequirefrequentmonitoringinnewbornsbecauseoftherapidlychangingphysiologicvaluesofthevitaminK-dependentproteins,thefrequentchangesinmedications,andthechangesindiet.Poorvenousaccessbecomesanissueforthesenewborns.Fourth,althoughthereissubstantialinformationontheuseofVKAsinchildrenwhoare?3monthsofage,thereisessentiallynoefficacyorsafetyinformationontheiruseinneonates.

Therapeuticrange

ForchildrenreceivingVKAs,thecapacityoftheirplasmastogeneratethrombinisdelayedanddecreasedby25%comparedtoplasmasfromadultswithsimilarINRs.78ThelattersituationraisestheissueofwhethertheoptimalINRtherapeuticrangeforchildrenwillbelowerthanthatforadults.Thishypothesisisfurthersupportedbytheobservationthatplasmaconcentrationsofamarkerofendogenousthrombingeneration,prothrombinfragment1.2,aresignificantlylowerinchildrencomparedtothoseinadultsatsimilarINRvalues.78

Despitethis,currenttherapeuticINRrangesforchil-drenaredirectlyextrapolatedfromrecommendationsforadultpatientsbecausenoclinicaltrialshaveassessedtheoptimalINRrangeforchildrenbasedonclinicalout-comes.

Doseresponse

Aninitialdoseof0.2mg/kg,withsubsequentdoseadjustmentsmadeaccordingtoanomogramusingINRvalues,wasevaluatedinaprospectivecohortstudy(Table5).1Thepublishedage-specific,weight-adjusteddosesforchildrenvaryduetothedifferentstudydesignsandpatientpopulations,andpossiblythesmallnumberofchildrenstudied.Thelargestcohortstudy(319patients)foundthattomaintainatargetINRof2to3infantsrequiredanaverageof0.33mg/kgwarfarinandthat

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TableToMaintain5—ProtocolanINRforBetweenOralAnticoagulationTherapyPatients*

2and3forPediatric

StageINR

Action

IDay11.0–1.3

0.2mg/kgorally

II

Days2–4

1.1Repeatday1loadingdose–1.31.450%ofday1loadingdose–1.92.050%ofday1loadingdose–3.03.125%ofday1loadingdose–3.5?3.5

HolddosinguntilINRis?3.5thenrestartaccordingtostageIIIguidelinesIII

Maintenance

1.1Increaseby20%ofdose–1.41.5Increaseby10%ofdose–1.92.0Nochange

–3.03.1Decreaseby10%ofdose–3.5?3.5

HolddosinguntilINRis?3.5thenrestartat20%lessthanlastdose

*ReproducedwithpermissionofMichelsonetal.3

teenagersrequired0.09mg/kgwarfarin.79Foradults,theweight-adjusteddosesforVKAsarenotpreciselyknownbutareintherangeof0.04to0.08mg/kgforanINRof2to3.37Themechanismsresponsiblefortheagedepen-dencyofVKAdosesarenotcompletelyclear.

Monitoring

Themonitoringoforalanticoagulanttherapyinchil-drenisdifficultandrequiresclosesupervisionwithfre-quentdoseadjustments.1,79Incontrasttoadults,only10to20%ofchildrencanbesafelymonitoredmonthly.1Thereasonscontributingtotheneedforfrequentmonitoringhavebeendescribedpreviously.

Point-of-caremonitoringinneonatesandchildrenWhole-bloodmonitorsusevarioustechniquestomea-surethetimefromtheapplicationoffreshsamplesofcapillarywholebloodtothecoagulationofthesample,andtoreportanINRvalue.Themonitorsincludeabatch-specificcalibrationcodethatconvertstheresultintoacalculatedINR.Therearetwo“point-of-care”monitorsthathavebeenevaluatedinthepediatricpopulation(CoaguChek;Boehringer-Mannheim;Mannheim,Germa-ny;andProTimeMicrocoagulationSystem;InternationalTechnidyneCorp;Edison,NJ).Bothmonitorshavebeenshowntobeacceptableandreliableforuseintheoutpatientlaboratoryandinhomesettings.Parentsand

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patientsundertookaformaleducationprogrampriortousingthemonitors.Themajoradvantagesidentifiedbyfamiliesincludedreducedtraumafromvenipunctures,minimalinterruptionofschoolandwork,easeofopera-tion,andportability.2,77,80Atthistime,nostudieshavedemonstratedtheaccuracyofpoint-of-caremonitorsforheparinorLMWHtherapy.

AdverseeffectsofVKAs

BleedingisthemaincomplicationofVKAs.TheriskofseriousbleedinginchildrenreceivingVKAsformechan-icalprostheticvalvesis?3.2%perpatient-year(13caseseries).81Inonelargecohortstudy(391warfarinyears,variabletargetrange),79thebleedingratewas0.5%perpatient-year.Inarandomizedtrial(41patients;targetINRrange,2to3[for3months]),69bleedingoccurredin12.2%ofpatients(95%CI,4.1to26.2).Nonhemorrhagiccom-plicationsofVKAs,suchastrachealcalcificationorhairloss,havebeendescribedonrareoccasionsinyoungchildren.82,83Twocohortstudies84havedescribedreducedbone?the1year.densityroleofHowever,inchildrenwhohavereceivedwarfarinfortheunderlyingtheseweredisordersuncontrolledinreducingstudies,boneanddensityremainsunclear.84

TreatmentofVKA-inducedbleeding

InthepresenceofahighINR(usually?8)andnosignificantbleeding,vitaminKmaybeusedtoreversetheeffectsofexcessanticoagulation.Thereareonlylimiteddata?g/kgavailablehavebeeninchildren,usedpreviously.butIVvitaminKindosesof3085Inthepresenceofsignificantbleeding,immediatereversalusingfresh-frozenplasma(FFP),prothrombincomplexconcentrates,orrecombinantfactorVIIamayberequired.Alternativethrombininhibitors

Asmallnumberofcasereports56,58,62,63,86havedocu-mentedtheuseofdanaparoidsodium,hirudin,andar-gatrobaninpediatricpatients.Themostcommonindica-tionhasbeenforthemanagementofHIT.Nofurtherdataareavailableatthistime.Astandardprotocolfordanap-aroidsodium(Orgaran)useisavailable(Table6).81

Antiplateletdrugsinneonatesandchildren

Background.Comparedtoadultcontrols,neonatalplateletsarehyporeactivetothrombin,adenosinediphos-phate(ADP)/epinephrine,andthromboxaneAofneonatalplateletsistheresult2.87,88Thishyporeactivityofadefectthatisintrinsictoneonatalplatelets.87,88Paradoxically,thebleedingtimeisshortinnewbornsduetoincreasedRBCsize,highhematocrit,andincreasedlevelsandmultimericformsofvonWillebrandfactor.89–91Thebleedingtimehasbeenshowntobeprolonged,relativetoadults,throughoutchildhoodintwoofthreestudies.92–94

Aninvitromethodusingadevice(PFA-100;DadeInternational;Miami,FL)forassessingprimaryhemosta-sisthatutilizescitratedwholebloodhasbeenstudied.102Thisinstrumentmeasuresthetimerequiredforaplatelet

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Table6—ProtocolforthePatientsUse*

ofOrgaraninPediatric

DosingDescriptionLoadingdose30U/kgbodyweightIVInitialmaintenancedose1.2–2.0U/kg/hIVMonitoringAnti-FXaactivitycanbemonitored

immediatelyafterbolusdose,every4huntilsteadystateisreached,thendailytomaintainatherapeuticrangeof0.2–0.8U/mL429*Orgaranconsistsmainlyofheparansulfate,asmallquantityofdermatansulfate,andaminoramountofchondroitinsulfate,anddoesnotcontainanyheparinfragments.Orgaranhasamuchhigheranit-FXa/anti-factorIIaratiocomparedtoheparinorLMWH.Orgaranhasadecreasedcross-reactivityrate(?10%)withheparin-inducedantibodycomparedtothatwithLMWH(?90%).40Orga-ranispredominantlyremovedfromthecirculationthroughthekidneys.Consequently,itsuseiscontraindicatedinpatientswithsevereimpairedrenalfunction.AlthoughsubcutaneousOrgaranisfrequentlyusedinadults,60nopediatricdoseinformationhasbeenpublished.

plugtooccludeanaperture(150?m)inamembranethathasbeencoatedwithfibrillartypeIcollageninthepresenceofeitherepinephrine(10?M)orADP(50?M)[ie,calledclosuretime].Plateletsareactivatedbyexposuretotheseagonistsandbyhighshearstressasthebloodisaspiratedthroughthemembraneaperture.Closuretimescorrelatewithhematocrit,quantitativeandfunctionallevelsofvonWillebrandfactor,andthenumberandfunctionalactivityofplatelets.104,105,Cordbloodsamplesfromtermneonateshaveshorterclosuretimesthandosamplesfromolderchildrenoradults.103,106,107TheshorterclosuretimecorrelateswiththehigherhematocritandincreasedvonWillebrandfactoractivity(measuredbytheristocetincofactorassay)incordblood.106

Aspirin

Aspirinremainsthemostcommonantiplateletagentusedinchildren.

Therapeuticrange,doseresponse,andmonitoring.Evidencefromstudiesofadults95–99hassuggestedthereissignificantinterindividualvariationinthedoseofaspirinrequiredforeffectiveantiplatelettherapy.Thedoseofaspirinrequiredfortheoptimalinhibitionofplateletaggregationisnotknown,althoughempiriclowdosesof1to5mg/kg/dhavebeenproposed.101Pediatricdosesofaspirinarenotbasedonstudiesoftheeffectonplateletfunctioninpediatricpatients.100Intheuseofthedeviceforassessingprimaryhemostasis(thePFA-100),theanti-plateletactionofaspirinprolongstheclosuretimewiththeepinephrinecartridgebutnotwithADP.Thedevicehasbeenshowntoquantifyanindividual’sresponsetoaspirintherapyandtobeeffectiveinmonitoringthecomplianceofaspirintherapyinadultpatients.110Itwilllikelybeusefulfordocumentingadequateaspirintherapyinpediatricpatients.81

Adverseeffects.Neonatesmaybeexposedtoaspirin

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asaresultofmaternalingestion(eg,treatmentforpre-eclampsia).Theclearanceofaspirinisslowerinneonates,potentiallyplacingthematriskforbleedingforlongerperiodsoftime.However,invitrostudieshavenotdemonstratedanadditiveeffectofaspirinonthehypo-functionofnewbornplatelets,andevidencelinkingma-ternalaspiriningestiontoclinicallyimportantbleedinginnewbornsisweak.Inneonates,additiveantiplateleteffectmustbeconsideredifconcurrentindomethacintherapyisrequired.

Inolderchildren,aspirinrarelycausesclinicallyimpor-tanthemorrhaging,exceptinthepresenceofanunderly-inghemostaticdefectorinchildrenwhoalsohavebeentreatedwithanticoagulantorthrombolytictherapy.Therelativelylowdosesofaspirinusedasantiplatelettherapy,comparedtothemuchhigherdosesusedforanti-inflam-matorytherapy,seldomcauseothersideeffects.Forexample,althoughaspirinisassociatedwithReyesyn-drome,thisappearstobeadose-dependenteffectofaspirinandisusuallyassociatedwithdosesof?40mg/kg.108,109,111–114

Treatmentofbleedingduetoantiplateletagents.Antiplateletagentsalonerarelycauseseriousbleedinginchildren.Morefrequently,antiplateletagentsareoneofseveralothercausesofbleedingsuchasanunderlyingcoagulopathyandotherantithromboticagents.Transfu-sionsofplateletconcentratesand/ortheuseofproductsthatenhanceplateletadhesion(plasmaproductscontain-inghighconcentrationsofvonWillebrandfactor,ordes-amino-D-argininevasopressinmaybehelpful.

Otherantiplateletagents

Thesecondmostcommonlyusedantiplateletagentinchildrenisdipyridamoleindosesof2to5mg/kg/d.115–117

Ticlopidineandclopidogrelarethienopyridines.BothdrugsselectivelyinhibitADP-inducedplateletaggregationviatheinhibitionoftheP2Y12receptor.118–120Theanti-plateleteffectofticlopidineandclopidogrelisadditivetothatofaspirin.121Therehasbeennoreporteduseinchildren,anddosagerecommendationsareunknown.Theclinicallyavailableglycoprotein(GP)IIb-IIIaan-tagonistsareIVabciximab,eptifibatide(Integrilin;Millen-nium;Cambridge,MA),andtirofiban(Aggrastat;Merck;WhitehouseStation,NJ).122Thesedrugs,whichareeitherchimericantibodyfragments(abciximab),peptides(epti-fibatide),ornonpeptidesmallmolecules(tirofiban),actbybindingtoplateletsurfaceGPIIb-IIIa(integrin?-IIb?blockingfibrinogen-mediatedplateletaggrega-3),therebytion.BecausefibrinogenbindingtotheplateletGPIIb-IIIaisthefinalcommonpathwayofplateletaggregation,thesedrugsarepowerfulantiplateletagents.122Inonestudy,123childrenwithKawasakidiseasewhoweretreatedwithabciximabinadditiontostandardtherapydemon-stratedgreaterregressionincoronaryaneurysmdiameteratearlyfollow-upthandidpatientswhoreceivedstandardtherapyalone.Thisstudycomparedabciximabtohistoricalcontrolsubjects,andallpatientsreceivedadditionalanti-coagulationtherapy.

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Thrombolyticagentsandthrombectomyinneonatesandchildren

Background.Theactionsofthrombolyticagentsaremediatedbyconvertingendogenousplasminogentoplas-min.Atbirth,plasmaconcentrationsofplasminogenarereducedto50%ofadultvalues(21mg/100mL).31,32,124Thedecreasedlevelsofplasminogeninnewbornsslowsthegenerationofplasmin125andreducesthethrombolyticeffectsofstreptokinase(SK),urokinase(UK),andtissueplasminogenactivator(tPA)inaninvitrofibrinclotsystem.128Asimilarresponseoccursinchildrenwithacquiredplasminogendeficiency.Thesupplementationofplasmaswithplasminogenincreasesthethrombolyticef-fectofallthreeagents.127,128

Therearenostudiesthatcomparetheefficacy,safety,orcostofdifferentthrombolyticagentsinchildren.Al-thoughSKisthecheapestofthethreeagents,SKhasthepotentialforallergicreactionsandmaybelesseffectiveinchildrenwithphysiologicoracquireddeficienciesofplas-minogen.

tPAhasbecometheagentofchoiceinpediatricpatientsforseveralreasons,includingtheFoodandDrugAdmin-istrationwarningregardingUK,experimentalevidenceofimprovedclotlysisinvitrocomparedtothatusingUKandSK,fibrinspecificity,andlowimmunogenicity.129,136How-ever,tPAisconsiderablymoreexpensivethaneitherSKorUK,andtheincreasedinvitroclotlysisbytPAhasnotbeendemonstratedinclinicaltrialsinchildren.Thereisminimalornoexperiencewiththeuseofotherthrombo-lyticagentsinchildren.

SuccessratesfortPAinpediatricpatientsvaryintheliterature.Aprospectivestudy130using0.5mg/kg/hsys-temictPAfor6hconcurrentlywithheparin(10U/kg/h)andFFPsupplementationpriortotPAinfusionreportedcompletethrombosisresolutionin13of20patients(65%)[arterialthrombosis,12patients;venousthrombosis,1patient],partialresolutionin4patients(20%)[arterialthrombosis,1patient;venousthrombosis,3patients],andnoresponsein3patients(15%)[arterialthrombosis,1patient;venousthrombosis,2patients].Zenzetal131reportedusingadoseof0.5mg/kg/hforthefirsthourfollowedby0.25mg/kg/huntilclotlysisoccurredortreatmenthadtobestoppedbecauseofbleedingcompli-cations.Completeclotlysiswasachievedin16of17patientswithin4to11hafterthestartoftreatment.Inonepatient,onlypartiallysisoccurred.Aftercompletelysis,rethrombosisdevelopedinonepatient15haftertheendoftreatment.

Contraindications.Therearewell-definedcontrain-dicationstothrombolytictherapyinadults.Theseincludeahistoryofstroke,transientischemicattacks,otherneu-rologicdisease,andhypertension.126Similarproblemsinchildrenshouldbeconsideredasrelativebutnotabsolutecontraindicationstothrombolytictherapy.

Therapeuticrangeandmonitoringofthrombolyticagents.Thereisnotherapeuticrangeforthrombolyticagents.Thecorrelationbetweenhemostaticparametersandtheefficacy/safetyofthrombolytictherapyistooweaktohaveusefulclinicalpredictivevalue.126However,in

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patientswithbleeding,thechoiceanddosesofbloodproductscanbeguidedbyappropriatehemostaticmoni-toring.Thesinglemostusefulassayisthefibrinogenlevel,whichusuallycanbeobtainedrapidlyandhelpstodeterminetheneedforcryoprecipitateand/orplasmareplacement.Acommonlyusedlowerlimitforfibrinogenlevelis100mg/dL.TheaPTTmaynotbehelpfulinthepresenceoflowfibrinogenlevels,concurrentheparintherapy,andthepresenceoffibrin/fibrinogendegradationproducts.126Measurementsoffibrinogendegradationproductsand/ord-dimersarehelpfulindeterminingwhetherafibrinolyticeffectispresent.

Doseresponse.Thrombolyticagentsareusedinlowdoses,usuallytorestorecatheterpatency,andinhigherdosestolyselarge-vesselTEsorPEs.Table7presentsthemostcommonlyusedlocalandsystemicdoseregimensforthrombolytictherapyinpediatricpatients.Theseprotocolscomefromcaseseries.127,132TheoptimaldosesforUK,SK,andtPAarenotknownforpediatricpatients.BasedontheresultsoftheThrombolysisinMyocardialInfarc-tionIItrial,133dosesof150mgrecombinantt-PAcausedmorebleedsintotheCNSthandiddosesof100mg(1.5%vs0.5%,respectively).Thesedatasuggestthatthereisanupperdoselimitbasedonsafety.

Routeofadministration.Therearenopublishedstudiesthathavecomparedlocalthrombolytictherapytosystemicthrombolytictherapyinchildren.134Atthistime,thereisnoevidencetosuggestthatthereisanadvantageoflocaloversystemicthrombolytictherapyinchildrenwiththromboticcomplications.Inaddition,thesmallvesselsizeinchildrenmayincreasetheriskoflocalvesselinjurywithnewthrombusformation.Localtherapymaybeappropriateforthetreatmentofcatheter-relatedTEswhenthecatheterisalreadyinsitu.Thereareisolatedcasereports135ofthrombolysisviauseofmultiple-lumencathetersinchildren.Therearenoreportedcasesofpulse-spraythrombolysisinchildren.

Adverseeffectsofthrombolytictherapy.Thrombo-lytictherapyhasbeenreported136tohavesignificantbleedingcomplicationsinchildren,occurringin68%ofpatients,withbleedingrequiringtransfusionoccurringin39%.Theprolongeddurationofthrombolyticinfusionwasassociatedwithincreasedbleeding.Zenzetal,131inaprospectivestudyusingtheprotocoldescribedearlier,reportedbleedingrequiringtransfusionin3of17patients(18%)whohadbeentreatedforbetween4and11h,andminorbleedingin9of17patients(54%).Anotherrecentprospectivestudy130usingadefinedprotocol,thekeyfeaturesofwhichwere(1)concurrentheparintherapy(10U/kg/h),(2)fixedtPAinfusionsat0.5mg/kg/hfor6hwithnoextensionsbeyond6h,and(3)FFP(10mL/kg)givenahalf-hourbeforeeachtPAinfusiontoensureadequateplasminogenandfibrinogenlevels,reportedbleedingrequiringtransfusionin2of20patients(10%),andminorbleedingepisodesin6patients(30%)[ie,venipuncturesitesandepistaxis].Earlierliteraturereviews127(including255patients)hadconcludedthattheincidenceofbleedingrequiringtreatmentwithpackedRBCswasapproximately20%inpediatricpatients.Themostfrequentproblemwas

SeventhACCPConferenceonAntithromboticandThrombolyticTherapy

Table7—ThrombolyticTherapyforPediatricPatients*

CVL

TreatmentLocalinstillationtPA

?10kg

Single-Lumen0.5mgdilutedin0.9%NaCltovolumerequiredtofillline

Double-Lumen0.5mgper

lumendilutedin0.9%NaCltofillvolumeofline;treatonelumenatatime1.0mg/mL;useamountrequiredtofillvolumeoflinetomaximumof2mL?2mgperlumen;treatonelumenatatime

SCPort0.5mgdilutedwith0.9%NaClto3mL2.0mgdilutedwith0.9%NaClto3mL

LoadingDose

Maintenance

Dose

Monitoring

?10kg

1.0mgin1.0mL0.9%NaCl;useamountrequiredtofillvolumeoflinetomaximumof2mL?2mg

SystemicthrombolytictherapyUK

4,400U/kg

4,400U/kg/hfor6–12h2,000U/kg/hfor6–12h0.1–0.6mg/kg/hfor6h

SK2,000U/kg

tPANone

Fibrinogen,TCT,PT,aPTTFibrinogen,TCT,PT,aPTTFibrinogen,TCT,PT,aPTT

*Startheparintherapyeitherduring,orimmediatelyuponcompletionofthrombolytictherapy.Aloadingdoseofheparinmaybeomitted.Thelengthoftimeforoptimalmaintenanceisuncertain.Valuesprovidedarestartingsuggestions,assomepatientsmayrespondtolongerorshortercoursesoftherapy.ReproducedwithpermissionofMichelsonetal.3TCT?thrombinclottingtime;PT?prothrombintime.

bleedingatsitesofinvasiveproceduresthatrequiredtreatmentwithbloodproducts.Inanotherreview,Zenzetal137reportedintracranialhemorrhage(ICH)in14ofthe929patients(1.5%)analyzed.Therewasnoinformationprovidedaboutconcurrentheparinadministrationinthisstudy.Whensubdividedaccordingtoage,ICHwasiden-tifiedin2of468children(0.4%)aftertheneonatalperiod,1of83terminfants(1.2%;95%CI,0.3to6.5%),and11of86preterminfants(13.8%;95%CI,6.6to21.7%).However,inthelargeststudyofprematureinfantsin-cludedinthisreview,theincidenceofICHwasthesameinpatientsinthecontrolarmofthestudy,whohadnotreceivedthrombolytictherapy.Aretrospectiveanalysisof16newbornswhoreceivedtPAreportedonedeathfrombleeding.138

Treatmentofbleedingduetothrombolytictherapy.Beforethrombolytictherapyisused,thecorrectionofotherconcurrenthemostaticproblemssuchasthrombo-cytopeniaorvitaminKdeficiencyisadvised.Clinicallymildbleeding,whichisusuallyoozingfromawoundorpuncturesite,canbetreatedwithlocalpressureandsupportivecare.Majorbleedingfromalocalsitecanbetreatedbystoppingtheinfusionofthethrombolyticagent,administeringacryoprecipitate(usualdose,1bagper5kg,or5to10mL/kg),andadministeringotherbloodproductsasindicated.Ifthebleedingislife-threatening,anantifi-brinolyticagentalsocanbeused.

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SurgicalTherapy

Inadditiontopharmacologictherapy,venousinterrup-tiondevices(ie,inferiorvenacava[IVC]filters)areusedforspecificclinicalindicationsinadults.Ahandfulofanecdotalreports139ofsuccessfulandfailedIVCfiltersinchildrenhavebeenpublished.Incontrasttoadults,temporaryIVCfiltersareoftenusedinchildrenandareremovedwhenthesourceofPEisnolongerpresent.140Recently,thesafetyoftemporaryIVCfiltershasbeendescribedinacaseseriesof10patients.141Therearenospecificguidelinesfortheuseoffiltersinchildren,andtherisk/benefitrationeedstobeconsideredindividuallyineachcase.

Surgicalthrombectomyisrarelyusedastreatmentinchildren.ThecommonsituationsinwhichthrombectomyisreportedincludeIVCthrombosisinassociationwithintravascularextensionofWilmtumor,acutethrombosisofBlalock-Taussig(BT)shunts,life-threateningintracar-diacthrombosisimmediatelyaftercomplexcardiacsur-gery,prostheticvalvethrombosis,andperipheralarterialthrombosissecondarytovascularaccessinneonates.Therearenocontrolleddatatocomparethevalueofconservativetherapy,anditisunlikelythatsuchdatawillbecomeavailable.Inmostcases,concurrentorsubse-quentanticoagulationtherapywasused.142–146Therearenospecificguidelinesfortheuseofthrombectomyin

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children,butthereisgeneralconsensusthatinmanysituationstheTErecurrencerateandtheriskoflong-termvasculardamagearehigh.However,therisk/benefitrationeedstobeconsideredindividuallyineachcase.

ThrombophiliaMarkers

Congenitalthrombophiliaisusuallydefinedashavingthefollowingfeatures:(1)positivefamilyhistory;(2)earlyageofonsetofTE;(3)recurrentdisease;and(4)TEinmultipleorunusuallocations.Clinically,themostsignifi-cantinheritedprothromboticconditionsaredeficienciesofAT,proteinC(PC),andproteinS(PS)becauseofthelargeincreaseinrelativerisk(RR)thatthesedeficienciesconfer.ActivatedPCresistance/factorVLeiden(FV-R506Q)andprothrombinG20210A(IIG20210A)poly-morphisms,whilehavinglessimpactonindividualrisk,aresignificantbecauseoftheirfrequenciesincertainpopula-tions.Alargenumberofothercandidategeneshavebeenproposed147asriskfactorsforcongenitalthrombophilia.However,mostofthesecandidateshavenotundergonecarefulsegregationorpopulationstudiestodefinetheirpathogenicrole.Infact,someoftheseeminglyobviouscandidatessuchasabnormalitiesinfibrinolysisdonotappeartoconferthromboticrisk.148However,theselatterstudiesarehamperedbythelowprevalenceofmostoftheseinheritedabnormalitiesinthegeneralpopulation.Somereports149havedemonstratedanincreasedriskforthrombosisinfamilieswithasecondgeneticabnor-mality.MostreportshavedescribedacombinationofFV-R506QwithabnormalitiesofPC,PS,andAT.Thesefindingsbegintoshedlightonthemarkedvariabilityinclinicalexpressionofthesesyndromes.Theeffectofmoreseveredeficiencieshaslongbeenevidentfromthese-verelyaffectedneonateswithhomozygousPCandPSdeficiencies.Apartfromthewell-definedhomozygouscases,theriskandseverityofTEsappeartovarywiththetypeandnumberofunderlyinggeneticabnormalities.149–152Thrombophiliamarkersinneonateswiththrombosis

Homozygousprothromboticdisordersusuallypresentinnewbornswithsevereclinicalmanifestationsthatmayhavedevelopedantenatallyandrequirespecificurgenttherapy.Thediagnosisofheterozygouscongenitalpro-thromboticdisordersinneonatescanbeproblematicbecausephysiologicvaluesaresignificantlydecreasedcomparedtothoseinolderchildrenandadults.31,33,92Thisissueisfurtherconfoundedbythepresenceofacquireddisordersthatarepresentin?80%ofneonateswithsystemicTEs,andthesedisordersfrequentlyhaveaconsumptivecomponentresultinginfurtherdecreasesintheseproteins.Althoughneonateswithheterozygotein-hibitordeficienciesrarelydevelopTEs,?20%ofneo-nateswithTEsareheterozygoteforacongenitalpro-thromboticdisorder.153Whetherthepresenceoftheseprothromboticmarkersshouldaffectthedurationofanti-coagulationtherapyandsubsequentsecondaryprophylaxisremainsundetermined.Inaddition,heterozygousinhibi-tordeficiencieshavebeenimplicatedinotherneonatal

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conditionssuchasporencephaly.Furtherstudiesarerequiredtoconfirmtheseassociations.154

Thrombophiliamarkersinchildrenwiththrombosis

Thereportedincidenceofcongenitalprothromboticdisorders?60%.inchildrenwithvenousTEsvariesfrom?1to150–152,154–186IfoneconsidersthedeficienciesofAT,PC,andPSinadditiontothefactorVLeidenandprothrombingenemutations,largefamilystudieshavefoundnegligibleratesofthrombosisinchildren?15years.187Anumberofcohortstudies163,165,167,180havefailedtoidentifyATdeficiencyinchildrenwithbotharterialandvenousTEs.ThosestudiesthathavereportedhigherfrequenciesofATdeficiencyhavenotdistin-guishedbetweenacquiredandinheriteddeficiencies.164InchildrenwithcancerandvenousTEs,thereportedincidenceofthrombophiliasis3%.180,188Thereisasimilardisparitybetweenstudiesconcerningthrombophiliaandchildhoodstroke.162–164,168–170,189–191Thevariabilityinin-cidencereportedinallofthesestudiesreflectssmallsamplesizes,variabilityinstudydesign,differingdefini-tionsofprothromboticdisorders,anddifferentpatientselection.192Mostrecently,aprospectivestudy193ofanunselectedcohortofchildrenwithvenousthrombosisfoundthat,withtheexceptionofteenagerswithsponta-neousthrombosis,inheritedthrombophilicmarkersdidnotcontributesignificantlytothepathogenesisofvenousthrombosisinchildren.

ScreeningforcongenitalprothromboticdisordersinchildrenwithvenousTEsisofunprovenbenefit,regard-lessofthepresenceorabsenceofacquiredriskfactors.Atthistime,theuniformscreeningofchildrenwithmajorillnesses,orofthosewhorequirecentralvenouslines(CVLs)inordertoprovideprophylactictherapyforthetreatmentofcongenitalprothromboticdisorderscannotberecommended.Thecontributionofcongenitalpro-thromboticdisorderstotheoccurrenceofvenousTEinpediatricpatientsremainstobeclarified.Fewchildrendevelopthrombosisduetoaheterozygotecongenitalprothromboticconditionwithoutalsohavinganacquiredriskfactor.147,161,186,194–201Neonateswhopresentwithpur-purafulminansorseverespontaneousthrombosisneedtohavehomozygousthrombininhibitordeficienciesex-cluded.

1.0SpecificIndicationsforAntithromboticTherapy

Thefollowingsectiondescribestheevidencefortheuseofanticoagulationtherapyinspecificclinicalcircum-stances.Inaddition,thereremainanumberoflesscommonclinicalsituationsinneonatesandchildreninwhichthequestionofoptimalantithromboticmanage-mentisimportant,however,theliteratureconsistsofonlyafewcasereports,suchthatthereareinsufficientdatatodistinguishbetweenanyofthepotentialtherapeuticop-tions.Oneexampleofsuchasituationisportalveinthrombosis,which,inneonates,mostcommonlyoccurssecondarytotheplacementofanumbilicalveincatheter

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(UVC),withorwithoutinfection.202–204Inolderchildren,portalveinthrombosisisrelatedtolivertransplantation,intra-abdominalsepsis,splenectomy,sicklecellanemia,andthepresenceofantiphospholipidantibodies.205–212Inapproximately50%ofchildrenwithportalveinthrombo-sis,anunderlyingetiologyisnotidentified.206,213,214Incontrasttoadultswithportalveinthrombosis,whichismostfrequentlysecondarytocirrhosis,liverfunctionisusuallynormalinchildren.210Thesedifferencesinetiologyandpathophysiologyreducetheusefulnessoftheextrap-olationoftherapeuticguidelinesforadultswithportalveinthrombosis,andyettheinfrequencyofitsoccurrenceinchildrensignificantlyhindersobtainingevidencethatwouldpermitinformedpediatricguidelinesfortherapy.1.1Systemicvenousthrombosisinneonates

Background

Aninternationalregistryofsymptomaticvenousthrom-boembolism(VTE)inneonatesreportedanincidenceof2.4per1,000admissionstoneonatalICUs.215AGermanprospective,nationwide,2-yearregistry153reportedanincidenceofsymptomaticneonatalTE(whichincludedCNSevents)tobe0.51per10,000births,withapproxi-matelyhalfofthecasesbeingVTEandhalfbeingarterialthrombosis.

Over80%ofcasesofVTEinnewbornsaresecondarytotheplacementofCVLs.215CVLsareusuallyplacedeitherintoumbilicalveins(ie,UVC)orintotheuppervenoussystemthroughperipheralveinsfromthearmorthroughmajorvesselssuchasjugularveins.Currently,UVCsorCVLsareusedextensivelyinprematureandfull-terminfantswhorequiresupportivecareintheformoffluids,drugs,ortotalparenteralnutrition(TPN).ThereareseveralmechanismsbywhichCVLscauseTEs,includingdamagetovesselwalls,216disruptedbloodflow,theinfu-sionofsubstancessuchasTPNthatdamageendothelialcells,217andthrombogeniccathetermaterials.218

Thereareseveralstudies219–222thathaveassessedtheincidenceofUVC-relatedVTE.Autopsystudies219,222–224haveestimatedtheincidenceofUVC-relatedVTEat20to65%ofneonateswhodiewithaUVCinplace.Clinicalstudies222haveestimatedtheincidenceofUVC-relatedVTEtobeapproximately13%.

Therearenumerousstudies225reportingtheriskofCVLTEbasedonthelossofCVLpatencyand/ortheresultsofobjectivetests.AlthoughthereisnodefinitivestudydeterminingtheincidenceofCVL-relatedVTEinneonates,thepublishedstudiesclearlyidentifyCVLsasthemostimportantriskfactor.

Theclinicalsymptoms/complicationsofVTEcanbeclassifiedasacuteorchronic.Theacuteclinicalsymptoms,besidesthelossofCVLpatency,includeswelling,pain,discolorationoftherelatedlimb,swellingofthefaceandheadwithsuperiorvenacavasyndrome,226andrespiratorycompromisewithPE.153,215Thechronicclinicalsymp-toms/complicationsincludeprominentcollateralcircula-tionintheskinoverthechest,back,neck,andface,therepeatedlossofCVLpatencyrequiringtreatmentwithlocalthrombolytictherapy,therepeatedrequirementforCVLreplacement,theeventuallossofvenousac-www.chestjournal.org

cess,CVL-relatedsepsis,chylothorax,227,228chylopericar-dium,229recurrentVTEnecessitatinglong-termanticoag-ulationtherapywithitsassociatedriskofbleeding,230andpost-thromboticsyndrome(PTS).231Specificlong-termsequelaeofUVC-relatedVTEincludeportalhyperten-sion,232splenomegaly,233gastricandesophagealvarices,majorbleedingrelatedtothevarices,153,234andhyperten-sion.235

ThereisnopublishedinformationontheincidenceofrecurrentVTEinneonates.ThereisalsonopublishedinformationontheincidenceofPTSinneonates.Poten-tially,neonatesareatanincreasedriskforPTSbecausethefibrinolyticsystemisphysiologicallysuppressed.Thelong-termfollow-upofneonateswithVTEiscriticallyimportanttodeterminethefrequencyandseverityofPTS.

TreatmentofvenousTEinneonates

Thereareinsufficientdatatomakestrongrecommen-dationsaboutanticoagulationtherapyinthetreatmentofnewbornswithDVTandpulmonarythromboembolism.Theoptionsincludeconventionalanticoagulationtherapyinage-appropriatedoses,short-termanticoagulationther-apy,orclosemonitoringofthethrombuswithobjectivetestsandtheuseofanticoagulationtherapyifthrombusextensionoccurs.Thetreatmentineachneonateshouldbeindividualizedwithdueconsiderationtotherisk/benefitratio.

Recommendations:NeonatesWithVTE

1.1.1.WesuggesttreatmentwitheitherUFHorLMWH,orradiographicmonitoringandanticoagulationtherapyifextensionoccurs(Grade2C).

1.1.2.Wesuggestthatifclinicianselectanticoagulationtherapy,theyadministerUFHorLMWH,andsubse-quentlyadministerLMWHfor10daysto3months(Grade2C).

1.1.3.WesuggestthatcliniciansadjustthedoseofUFHtoprolongtheaPTTcorrespondingtoananti-FXalevelof0.35to0.7U/mL(Grade2C).

1.1.4.WesuggestthatcliniciansadjustthedoseofLMWHtoachieveananti-FXalevelof0.5to1.0U/mL.(Grade2C).

1.1.5.Wesuggestthatifthethrombusextendsfollowingthediscontinuationofheparintherapy,cliniciansadmin-isterVKAsorextendedLMWHtherapy(Grade2C).1.1.6.WesuggestthatcliniciansnotusethrombolytictherapyfortreatmentofVTEinneonatesunlessthereismajorvesselocclusionthatiscausingacriticalcompro-miseoforgansorlimbs(Grade2C).Ifthrombolytictherapyisused,wesuggestsupplementationwithplasmino-gen(FFP)immediatelypriortothrombolysis(Grade2C).1.1.7.Wesuggestthat,ingeneral,cliniciansshouldremoveeitherCVLsorUVCsthatareinsitu.However,ifeitherCVLsorUVCsarestillinplaceatthecompletionoftheabovetherapy,wesuggestprophylacticdosingwithLMWHtopreventrecurrentVTEuntilsuchtimeastheCVLortheUVCisremoved(bothGrade2C).

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1.2Systemicvenousthromboembolicdiseaseinchildren

Background

TheestimatedincidenceofsymptomaticVTEinchil-drenis5.3per10,000hospitaladmissions.Severalmech-anismslikelycontributetotheprotectiveeffectofageforVTE.Theseincludeareducedcapacitytogeneratethrom-bin,39,40increasedcapacityof?antithrombotic2-macroglobulintoinhibitthrombin,236andtheenhancedpotentialofthevesselwall.237,238Ninety-fivepercentofVTEsinchildrenaresecondarytoseriousconditionssuchascancer,trauma/surgery,congenitalheartdisease(CHD),andsystemiclupuserythematosus.215,230,239–241TheagegroupsatgreatestriskforVTEareinfants?1yearofageandteenagers.215,230,242MostchildrenhaveseveralriskfactorsforVTEs,withthemostcommonriskfactorbeingthepresenceofaCVL.Themostfrequentnon-CVL-associatedVTEisinalowerlimb.242

Over50%ofVTEsinchildrenoccurintheuppervenoussystemsecondarytotheuseofCVLs.215,230,242TheincidenceofCVL-relatedVTEsreportedintheliteraturevaries,reflectingdifferentunderlyingconditions,theuseofdifferentdiagnostictests,anddifferentindexesofsuspicion.Forexample,theincidenceofCVL-relatedVTEinchildrenreceivinglong-termTPNvariesfrom1%(basedonclinicaldiagnosis)243,244to35%(basedonven-tilation-perfusionscansorechocardiography),to75%(basedonvenography).245Inaprospectivecohort,246,24718%ofchildreninanintensivecaresettingwithCVLsinplacefor48hdevelopedCVL-relatedVTE.TherecentlycompletedProphylacticAntithrombinReplacementinKidsWithALLTreatedWithL-Asparaginase(PARKAA)study17reporteda37%incidenceofvenographicallyprovenVTEinasymptomaticchildrenwithacutelympho-blasticleukemiawhowerereceivingL-asparaginasether-apy.Inmanypatientpopulations,theincidenceisnotaccuratelyknown.

Radiographicallydetected,asymptomatic,CVL-relatedVTEsinchildrenareofclinicalimportanceforanumberofreasons.First,thereisincreasingevidencethatCVL-relatedVTEsareassociatedwithCVL-relatedsepsis.Inameta-analysis,248prophylacticUFHtherapyreducedCVL-relatedVTE(RR,0.43;95%CI,0.23to0.78),andinadditiondecreasedbacterialcolonization(RR,0.18;95%CI,0.06to0.60)andprobablyCVL-relatedbacteremia(RR,0.26;95%CI,0.07to1.03).Second,CVL-relatedVTEsarethemostcommonsourceforPEinchildren,249whichmaybefatal.250Thelong-termconsequencesmaybesignificant,althoughtheirfrequencyisunknown.Casereports153,155,199havedocumentedsuddendeathresultingfromtheruptureofanintrathoraciccollateralvesselthoughttobeduetoapreviousCVLplacement.

IntheCanadianregistry,consistingof405pa-tients(meanfollow-up,2.86years),recurrentvenousTEsoccurredinapproximately8%ofchildren.250IntheDutchstudy,153therecurrenceratewas7%atthe1-yearfollow-up.

PTShasbeenestimated231tobepresentinupto65%ofchildrenpost-VTE,butclinicallysignificantPTSoccurs

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inapproximately10to20%ofchildren.234,250Thereis,asyet,noproperlyvalidatedoutcomemeasureforPTSinchildren.

Evidence

Therehasbeenonemulticenterrandomizedtrialofanticoagulationforvenousthrombosisinchildren.6TheREVIVE(ReviparinInVenousThromboembolism)trialrandomizedchildren(ie,those?3monthsofage)withafirstDVTtoreceiveeitherUFHandthenVKAs(targetINR,2.5)for3months,oranLMWH(reviparin)toatargetanti-FXalevelof0.5to1.0U/mLfor3months.6Theoutcomemeasureswererecurrenceduringnext3monthsaftertreatment.Thestudystoppedpriortothecompletionoftargetrecruitment,makingthestudyunderpowered(78patients)toanswertheprimaryquestion.However,therecurrencerateswere5.6%inthereviparinarmand12.5%intheUFH/VKAarm.Thestudyalsoreportedmajorbleedingratesof5.6%inthereviparinarmand12.5%intheUFH/VKAarm.

TheearlyclosureoftheREVIVEstudy,andthesubsequentlydescribedProphylaxisofThromboembolisminKidsTrial(PROTEKT)study,5highlightthedifficultiesofperformingmulticenterrandomizedtrialsinpediatricpatients.Bothstudieswereclosedearly.Theprimaryreasonfortheprematureclosurebythesponsorwasslowrecruitmentratesforeachstudy.However,theinitialinclusionandexclusioncriteriaweremodeledonadultantithromboticstudies,andprecludedmanyclinicallyrelevantpatients.Furthermore,consentrateswerelow,reflectingthecautiousnessofparents(andmanypediatri-cians)withrespecttorandomizedtrials.Thefollowingrecommendationsarebasedmostlyondatafromadultstudies,andtherelevantevidencecanbefoundintherelatedarticlesinthisvolume.

Recommendations

FirstTEforchildren?2monthsofage

1.2.1.WerecommendtreatmentwithIVheparinthatissufficienttoprolongtheaPTTtoarangethatcorrespondstoananti-FXalevelof0.35to0.7U/mL,ortreatmentwithLMWHthatissufficienttoachieveananti-FXalevelof0.5to1.0U/mL4hafteraninjection(Grade1C?).1.2.2.WerecommendinitialtreatmentwithheparinorLMWHfor5to10days(Grade1C?).ForpatientsinwhomsubsequentVKAswillbeused,werecommendbeginningoraltherapyasearlyasday1anddiscontinuingheparin/LMWHonday6iftheINRisinthetherapeuticrangeontwoconsecutivedays(Grade1C?).FormassivePEsorextensiveDVTs,werecommendalongerperiodofheparinorLMWHtherapy(Grade1C?).

1.2.3.WesuggestcontinuinganticoagulanttherapyforidiopathicTEsforatleast6months,usingVKAstoachieveatargetINRof2.5(INRrange,2.0to3.0)oralternativelyusingLMWHtomaintainananti-FXalevelof0.5to1.0U/mL(Grade2C).

Underlyingvaluesandpreferences:Thesuggestiontouse

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anticoagulationtherapytotreatidiopathicDVTsinchil-drenforatleast6monthsratherthanonalifelongbasisplacesarelativelyhighvalueonavoidingtheknownriskofbleedingsecondarytoanticoagulanttherapyinyoungactiveadultsandplaceslessimportanceontheunknownriskofrecurrenceintheabsenceofanongoingclinicalprecipitatingfactor.

1.2.4.Wesuggestthat,forsecondaryTEs,anticoagulanttherapybecontinuedforatleast3monthsusingVKAstoachieveatargetINRof2.5(INRrange,2.0to3.0)oralternativelyusingLMWHtomaintainananti-FXalevelof0.5to1.0U/mL(Grade2C).

1.2.5.Wesuggestthatinthepresenceofongoingriskfactors,suchasactivenephroticsyndrome,ongoingaspar-aginasetherapy,oralupusanticoagulant,anticoagulanttherapy,ineithertherapeuticorprophylacticdoses,con-tinueuntiltheriskfactorhasresolved(Grade2C).1.2.6.WesuggestthatcliniciansnotusethrombolytictherapyroutinelyforvenousTEinchildren(Grade2C).Treatmentneedstobeindividualized,andneedstobebasedonthesizeandlocationofthethrombus,andonthedegreeoforgancompromise.Ifthrombolytictherapyisused,inthepresenceofphysiologicorpathologicdefi-cienciesofplasminogen,wesuggestsupplementationwithplasminogen(FFP)[Grade2C].

RecurrentidiopathicTEsinchildren

1.2.7.WerecommendindefinitetherapywitheithertherapeuticorprophylacticdosesofVKAs(Grade1C?).WesuggestLMWHasanalternativeifVKAtherapyistoodifficult(Grade2C).

RecurrentsecondaryTEsinchildren

1.2.8.Wesuggestthat,followingtheinitial3monthsoftherapy,anticoagulationtherapybecontinuedforatleastafurther3months,oruntiltheremovalofanyprecipitat-ingfactors(Grade2C).

CVL-relatedthrombosis

TherearetwoaspectstothemanagementofCVL-relatedthrombosis.First,managementoftheCVLitselfand,second,anticoagulationtherapy.

1.2.9.WesuggestthatiftheCVLisnolongerrequired,orisnonfunctioning,itberemoved(Grade2C).Wesuggestatleast3to5daysofanticoagulationtherapypriortoitsremoval.IfCVLaccessisrequiredandtheCVLinvolvedisstillfunctioning,wesuggestthattheCVLremaininsitu(Grade2C).Anticoagulationtherapyshouldbegivenasdescribedinrecommendations1.2.1to1.2.6.

1.2.10.ForchildrenwithafirstCVL-relatedDVTaftertheinitial3monthsoftherapy,wesuggestthatprophy-lacticdosesofVKAs(INRrange,1.5to1.8)orLMWH(anti-FXalevelrange,0.1to0.3)begivenuntiltheCVLisremoved(Grade2C).

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1.2.11.ForchildrenwithrecurrentCVL-relatedTEsaftertheinitial3monthsoftherapy,wesuggestprophy-lacticdosesofVKAs(INRrange,1.5to1.8)orLMWH(anti-FXalevelrange,0.1to0.3)becontinueduntiltheremovaloftheCVL.Iftherecurrenceoccurswhilethepatientisreceivingprophylactictherapy,wesuggestcon-tinuingtherapeuticdosesuntiltheCVLisremovedorforaminimumof3months(Grade2C).1.3Renalveinthrombosis

Background

Renalveinthrombosis(RVT)isthemostcommonnon-catheter-relatedVTEinneonatesandisresponsibleforapproximately10%ofallVTEsinneonates.Almost80%ofallRVTspresentwithinthefirstmonthandusuallywithinthefirstweekoflife.9,153,254–257SomeneonatesdevelopRVTsinutero.254TheincidencesofRVTinmaleandfemaleneonatesaresimilar,bothsidesofthebodyareaffectedequally,andRVTsoccurbilaterallyin24%ofcases.254

TheetiologiesofRVTarediverseandreflecttheprevalenceofpathologicconditions,whichincludeperi-natalasphyxia,shock,polycythemia,cyanoticCHD,dia-beticmothers,dehydration,andsepticemia.Thesedisor-dersresultinreducedrenalbloodflow,increasedbloodviscosity,hyperosmolality,andhypercoagulability.254

Neonatesusuallypresentwithaflankmass,hematuria,proteinuria,thrombocytopenia,andnonfunctionoftheinvolvedkidney.However,inoneseries258of23cases,ofwhich83%werediagnosedinthefirstmonthafterbirth,thecompletetriadwasseeninonly13%ofneonates.ClinicalfindingssuggestiveofassociatedacuteIVC-relatedVTEincludecold,cyanotic,andedematouslowerextremities.Chronicobstructionischaracterizedbythedilationofcollateralveinsovertheabdomenandupperthighs,aswellasbilateralPTS.

TheoutcomeofRVThaschangedfromafrequentlylethalcomplicationtooneinwhich?85%ofneonatessurvive,mostlyduetoimprovementsinsupportivecareandmoresensitivediagnostictechniques,wideningthespectrumofdiagnosedcases.Atotalof58neonateswithrenalvenousthrombosishavebeenfollowedfor0.1to17yearsbyfourdifferentinvestigatorteams.Persistenthy-pertensionwasfoundin28%ofallchildren,and21%hadresidualrenaltubulardefects.259Inanotherstudy,26026of39affectedkidneyswereatrophic.Unfortunately,therearenorecentstudiesassessinglong-termmorbiditysuchashypertensionandlossofrenalfunction.

Evidence

TheonlydataonthetreatmentofRVTshavecomefromcasereportsandsmallseries.Therefore,theuseofanticoagulantorthrombolytictherapyiscontroversial.261Therearenodatatoconfirmthatactivetreatmentim-provesthelong-termoutcomeintheabsenceofacuterenalfailure.262–267

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Recommendations

1.3.1.ForunilateralRVTintheabsenceofuremia,andintheabsenceofextensionintotheIVC,wesuggestsupportivecarewithcarefulmonitoringoftheRVTforextension(Grade2C).Alternatively,wesuggestanticoag-ulationtherapywithUFHorLMWH(Grade2C).1.3.2.ForunilateralRVTthatextendsintotheIVC,wesuggestanticoagulationtherapywithUFHorLMWHfor6weeksto3months(Grade2C).

Remark:Thetherapeuticrangeisthesameasthatforvenousthrombosis.

1.3.3.ForbilateralRVTwithvariousdegreesofrenalfailure,wesuggesttherapywithUFH(andnotLMWH)andthrombolytictherapy(Grade2C).1.4CVLprophylaxis

Anumberofrandomizedtrialshavecomparedthrom-boprophylaxisvsnotreatmentforthepreventionofCVL-relatedDVTinadultswithcancer.Therapywithbothfixed-dosewarfarin(1mg)268anddalteparin(2,500U)269resultedinsignificantriskreductionwhenusingvenographyasthestudyendpoint.Inastudycomparingclinicalendpoints,VersoandAgnelli271reportednodifferenceinsymptomaticthrombosisbetweenpatientsreceivingdalteparin(5,000U)orplacebo.Mismettietal270comparedtherapywithnadroparin(2,850U)andwarfarin(1mg),andfoundnosignificantdifferenceinthrombosisfrequency.ThromboprophylaxisforadultswithcancerandCVLshasrecentlybeenreviewed.271

TherehasbeenonemulticenterrandomizedtrialofthromboprophylaxisforCVL-relatedDVTinchildren.ThePROTEKTstudyrandomized186childrenwithanewCVL(short-termorlong-term)toreceiveeitherthestandardofcareorLMWH(ie,reviparin,30U/kgsubcu-taneouslybid)untiltheCVLwasremovedorfor30days,whichevercamefirst.Allpatientsunderwentanexitvenogram.Thestudywasunderpoweredbecauseofpre-matureclosure.TheresultsshowedanincidenceofCVL-relatedDVTof13%inbotharmsofthestudy.Asmallprospectivecohortstudy272hassuggestedimprovedCVLsurvivalinchildrenreceivinglong-termhomeTPNwhoaremanagedwithprophylacticVKAtherapy(targetINR,1.3to1.8[ifnopreviousthrombosis]or2.0to3.0[ifpreviousthrombosis]).

Recommendations

1.4.1.ForchildrenwithCVLs,werecommendagainstroutineprimaryprophylaxis(Grade1B).

1.4.2.Forchildrenreceivinglong-termhomeTPN,wesuggestantithromboticprophylaxistherapy.WesuggesttheuseofVKAs(targetINR,2to2.5)continuouslyor,alternatively,forthefirst3monthsaftereachCVLisinserted(allGrade2C).

Remark:Theoptimaldruganddoseareunknown.

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1.5PrimaryprophylaxisforBTshuntsinneonatesBTshuntsareoneformofpalliativesurgeryusedtoenhancesystemic,subclavianartery,andpulmonaryarterybloodflowinpatientswithsevereorprogressivecyanosis,usuallysecondarytopulmonarystenosis.273,274“Modified”Blalockshunts,inwhichaplastic(Gortex;WLGore;Newark,DE)tubegraftistakenfromthesideofthesubclavianarteryandisanastomosedtothepulmonaryartery,havebeenusedsince1980.Becauseoftheshortlengthandveryhighflow,acutethrombosisislesscom-mon.Since1980,647childrenwithBTshuntshavebeenreportedin21caseseries.Theincidenceofthromboticocclusionrangedfrom1to17%.Manyinvestigatorshaveusedantithrombotictherapybeginningwiththerapeuticdosesofheparinandfollowedbylow-doseaspirin(1to10mg/kg/d),275althoughothershaverecommended276intra-operativeheparintherapywithnofurtheranticoagulationtherapy.

Recommendation

1.5.1.ForneonateswithBTshunts,wesuggestthattheyreceiveintraoperativetherapywithheparinfollowedbyeitheraspirin(5mg/kg/d)ornofurtheranticoagulanttherapy(Grade2C).

1.6Primaryprophylaxisforstage1Norwoodpro-ceduresinneonates

TheNorwoodprocedureisnowcommonlyperformedastheinitialsurgeryforchildrenwithhypoplasticleftheart,whichwaspreviouslyanalmostuniformlyfatalcondition.Thromboticcomplicationshavebeenreportedfollowingstage1Norwoodsurgery,277however,themajorcausesofpostoperativedeathremainsurgicalandhemo-dynamicfactors.278Thepotentialforthrombosistoin-creasepulmonarypressuresandsotorestrictthepotentialforsubsequentFontansurgeryisimportant.Therearenospecificstudiesexaminingtheroleofanticoagulationprophylaxis,althoughthecommonpracticeistouseheparinimmediatelypostoperativelyfollowedbyaspirin,asperBTshunts.Thedurationoftherapyandtheneedforongoingaspirintherapyareunknown.

Recommendation

1.6.1.ForpatientswhoundergotheNorwoodproce-dure,wesuggesttherapywithheparinimmediatelyaftertheprocedure(Grade2C).

1.7PrimaryprophylaxisforGlennorbilateralcavopulmonaryshuntinchildren

Glennsuccessfullyperformedtheclassiccavopulmo-naryanastomosisin1957aspalliationfortricuspidatresia.ThebidirectionalGlennshuntisnowfrequentlyusedasthefirststepinthetreatmentofpatientswithsingleventriclespriortodefinitiveFontansurgery.ThromboticcomplicationsfollowingplacementoftheGlennshuntareinfrequentlyreported.279–281Thereappeartobenodatatosupporttheneedforroutinethromboprophylaxis.How-SeventhACCPConferenceonAntithromboticandThrombolyticTherapy

ever,onceagain,thefactthatmanypatientssubsequentlyproceedtoFontanprocedureshasledtosomesuggestionsthatthromboprophylaxisiswarrantedafteraGlennshunttoreducetheriskofthrombosisinthepulmonaryvascu-lature,henceincreasingthelikelihoodofsuccessfulcon-versiontoafullFontancircuit.Currentclinicalpracticesvaryandincludethefollowing:noanticoagulationtherapy;therapywithheparinfollowedbyaspirintherapy;andtherapywithheparinfollowedbywarfarintherapy.Thereisnoevidencetosupportapreferenceforanyoftheseapproachesatthistime.

1.8PrimaryprophylaxisforFontansurgeryinchildren

TheFontanprocedure,oramodifiedversion,isthedefinitivepalliativesurgicaltreatmentformostcongenitaluniventricularheartlesions.TEsremainamajorcauseofearlyandlatemorbidityandmortality.ThereportedincidencesofvenousTEsandstrokehaverangedfrom3to16%andfrom3to19%,respectively,inretrospectivecohortstudiesinwhichthrombosiswastheprimaryoutcome,andfrom1to7%inretrospectivestudiesassessingmultipleoutcomes.TEsmayoccuranytimefollowingtheperformanceofFontanprocedures,butoftentheypresentmonthstoyearslater.Nopredisposingfactorshavebeenidentifiedwithcertainty,althoughthismaybeduetoinadequatepowerandtheretrospectivenatureofthestudies.Transesophagealechocardiographyismoresensitivethantransthoracicechocardiographyforthediagnosisofintracardiacandcentralvenousthrombo-sis.Despiteaggressivetherapy,TEsfollowingFontanprocedureshaveahighmortalityandrespondtotherapyin?50%ofcases.Thereisnoconsensusintheliterature,orinroutineclinicalpractice,astotheoptimaltypeordurationofanticoagulationtherapy.Consequently,awidevarietyofprophylacticanticoagulantregimesareinuse.Therehavebeenanumberofreviewsofthromboprophy-laxisfollowingFontanprocedures,andthereisanongoinglargemulticenterprospectivetrialofprophylacticantico-agulationtherapyfollowingFontanprocedures.282,283Thetrialcomparesaspirin(5mg/kg/d)toinitialtherapywithheparinfollowedbywarfarintherapy(targetINR,2to3)asprimaryprophylaxis.

Recommendation

1.8.1.ForchildrenafterFontansurgery,wesuggesttherapywithaspirin(5mg/kg/d)ortherapeuticheparinfollowedbyVKAstoachieveatargetINRof2.5(INRrange,2to3)[Grade2C].

Remark:Theoptimaldurationoftherapyisunknown.Whetherpatientswithfenestrationsrequiremoreinten-sivetherapyuntilfenestrationclosureisunknown.1.9Primaryprophylaxisforendovascularstentsinchildren

Endovascularstentsarebeingusedincreasinglytomanageanumberofcongenitalheartlesions,includ-ingbranchpulmonaryarterystenosis,pulmonaryvein

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stenosis,andcoarctationoftheaorta,andtotreatsubsequentsurgicalstenosis.284Althoughstentscanbesuccessfullyusedininfants?1yearofage,thesmallvesselsizeincreasestheriskofthrombosis.Therearenostudiesassessingtheroleofanticoagulationorantiplatelettherapytoavoidstentocclusioninchildren.Hepariniscommonlygivenatthetimeofstentinser-tion,followedbyaspirintherapy.Furtherstudiesarerequiredtodeterminetheoptimalrequirementforprophylacticanticoagulationtherapy.

Recommendation

1.9.1.Forchildrenhavingendovascularstentsinserted,wesuggesttheadministrationofheparinperioperatively(Grade2C).

1.10Primaryprophylaxisfordilatedcardiomyop-athyinneonatesandchildren

Theetiologyofcardiomyopathyinchildrenisquitedifferentfromthatseeninadults.Postviralandidiopathiccardiomyopathyoccurinotherwisewellchildren,whereasdilatedcardiomyopathyoccursfrequentlyduringtheendstageofmusculardystrophies.Theoutcomeisfrequentlypoor,withlongwaitsfortransplantableheartsformostchildren.285–289Inacross-sectionalstudy290ofchildrenawaitingcardiactransplants,31%weresaidtohaveacutePEsconfirmedbyventilation-perfusionscanningoran-giography.Therearenostudiesdemonstratingtheeffec-tivenessofanticoagulationprophylaxis.However,basedonadultstudies,andtheapparentriskofPEandstrokeinchildrenwithcardiomyopathy,anticoagulationtherapyiscommonlytheprimaryprophylaxis,usuallyusingwarfarintoatargetINRof2.5(INRrange,2to3).291

Recommendation

1.10.1.WesuggestthatchildrenwithcardiomyopathyreceiveVKAstoachieveatargetINRof2.5(INRrange,2to3).Suchtherapyshouldbeginnolaterthanwhenthechildisactivatedonacardiactransplantwaitinglist(Grade2C).

Underlyingvaluesandpreferences:OursuggestionfortheadministrationofVKAsplacesahighvalueonavoidingthromboticcomplications,andarelativelylowvalueonavoidingtheinconvenience,discomfort,andlimitationsofanticoagulantmonitoringinchildrenforwhomapoten-tiallycurativetherapy(fortheircardiomyopathy)isavail-able.

1.11Primaryprophylaxisforbiologicalprostheticheartvalvesinchildren

Valvularheartdiseasesinchildhoodencompassawidevarietyofabnormalitieswithgreatlyvariablepresenta-tions.Thevalvelesionmaybeisolated,anintegralpartofmorecomplexintracardiaclesions,ortheresultoftreat-mentoftheunderlyingcongenitaldefect.TEs,eitherofthevalveoraspartofacerebralvascularaccident,aresomeofthemostseriouscomplicationsofsuccessful

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cardiacvalvereplacement.Thefailureofbiologicalpros-theticheartvalvesinchildrenpoignantlyillustratesthefallacyofextrapolatingrecommendationsforadultstochildren,withoutevaluationinclinicaltrials.Commer-ciallypreparedbiologicalprosthesesbecameavailablein1971andachievedexcellentearlyresultsinadultpatients.Biologicalprostheticheartvalvesrapidlybecamethe“valveofchoice”forthepediatricagegroup.292Subse-quently,theprematuredegenerationandcalcificationofporcinevalveswasidentifiedinthemajorityofchil-dren.292–299Theacceleratedfailureofbiologicalprostheticheartvalvesinchildrenwasconfirmedbymanygroups.Thecurrentrecommendationsarethat,ingeneral,me-chanicalprostheticheartvalvesbeusedinthemitralandaorticpositionsinchildren,andthatbiologicalprostheticheartvalvesbereservedforpatientswhorequiretricuspidorpulmonaryvalvereplacements.300,301Childrenwithbiologicalprostheticheartvalvesaretreatedfollowingadultrecommendationsandareobservedforevidenceofvalvedysfunction.

ingadultguidelines(seethearticlebySalemetalinthissupplement)fortheintensityoftherapy(ie,targetINRs)[Grade1C?].

1.12.2.InchildreninwhomadditionalantithrombotictherapyisrequiredduetolackofresponsetoVKAsoracontraindicationfortheadministrationoffull-doseVKAs,wesuggestaddingaspirin(6to20mg/kg/d)[Grade2C].1.13Primaryprophylaxisforsurgery/immobiliza-tion(children)

Short-termprophylacticanticoagulationtherapyisanoptionforchildrenwhoareinhigh-risksituations,suchasimmobility,significantsurgery,ortrauma,andhavemul-tipleriskfactors(eg,astrongfamilyhistoryofthrombosisorpresenceofacentralvenousaccessdevice).However,therearenopublisheddataonwhichtobaseaformalrecommendation.Therisk/benefitrationeedstoconsid-eredforeachindividualpatient.Ageisanimportantconsideration,withlateadolescentslikelybeingatin-creasedriskcomparedtoinfants.Theoptimalprophylacticregimeinthissituationisunknown.

1.14Thromboprophylaxisforcardiaccatheteriza-tioninneonatesandchildren

Themostcommonaccesssiteforcardiaccatheteriza-tion(CC)isthefemoralartery,althoughbrachialarteriesareusedonsomeoccasions.Aseriouscomplicationoffemoralarterycatheterizationsislocalthrombusformationintheileofemoralsystem.Thethrombususuallybeginsatthepuncturesiteandextendsproximallyordistallyforvariablelengths.Thesubsequentinjurymayrangefromamilddecreaseinpulsestrengthasaresultofpartialobstructionbyathrombus,tosevereischemiaandpoten-tiallossoflimbsecondarytoasignificantinterruptionofarterialbloodflow.Theriskofseverevascularcomplica-tionsislinkedtotechnicaldifficultiesandincreasedcatheter/arterysizeratios.ArterialspasmusuallyresolveswithinafewhoursfollowingCC,whilemostTEsresolvefollowingtreatmentwithheparinorthrombolytictherapy.ArterialspasmorTEsthatrapidlyresolveareusuallyoflittleconcern.

Recommendation

1.11.1.Forchildrenwithbiologicalprostheticheartvalves,werecommendfollowingtheadultguidelines(seethearticlebySalemetalinthissupplement)[Grade1C?].

1.12Primaryprophylaxisformechanicalpros-theticheartvalvesinchildren

AntithrombotictherapywithVKAsisclearlyindicatedforadultswithmechanicalprostheticheartvalves.Alter-nativestoVKAshavebeenpursuedforchildrenbecauseoftheissueofsafemonitoring.Thestudiesdescribingtheuseofnotherapy,antiplateletagents,andoralanticoagu-lationtherapyareshowninTables8,9,and10,respec-tively.Insummary,thesedatasupporttherecommenda-tionfortheuseoftherapywithVKAsinchildrenwithmechanicalprostheticheartvalves,followingsimilarguidelinestothoseusedforadults.

Recommendations

1.12.1.Forchildrenwithmechanicalprostheticheartvalves,werecommendtheadministrationofVKAsfollow-

Table8—ThromboembolicandHemorrhagicComplicationsofMechanicalProstheticHeartValvesWithno

AntithromboticTherapy*

TE,%pt-yrNRNR5.76.820.027.3

HEM,%pt-yr000000

Study/YearSadeetal473/1988

LevelV

No.48

Age5mo–21yr

ValveTypeSt.Jude

PositionAo,MAo?MOverallAoM

?2valves

Deaths1?

Solymaretal116/1991V(186)?1–19yrVarious

*HEM?hemorrhage;Ao?aortic;M?mitral;NR?notreported;pt?patient.?Thedeathwassecondarytoamitralvalvethrombosis.

?Thenumberofpatientstreatedwithnoantithrombotictherapycouldnotbedetermined.(186)referstotheentirepatientpopulationofthestudy.116662S

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Table9—ThromboembolicandHemorrhageComplicationsofMechanicalProstheticHeartValvesTreatedWith

AntiplateletAgents*

Study/Year

Serraetal474/1987McGrathetal475/1987elMakhloufetal115/1987

LevelVVV

No.2430150

DoseASA,6mg/kg/d;DIP,25mg/kgASA,900mg/d;DIP,150mg/kg/dASA,20mg/kg/d;DIP,5mg/kg/d

Ages5–20yr4–20yr2–16yr

ValveTypeSt.JudeSt.JudeVarious

PositionAoMAo,M?2valvesAo,M?2valvesOverallAoMAo,M?2valvesAoMAoM

Ao,M,?2valves

TE,%pt-yr681932NRNRNR2.30121.82.5NR01.101.71.7

HEM,%pt-yrNRNR0?NRNRNR0.10?0?NRNRNR0?0?0?0?0

Deaths0001Ao?M

0000002CVAs001§0?0?2

Bradleyetal476/1985Solymaretal116/1991

VV

ASA,6.1mg/kg/d;DIP,1.9mg/kg/d

(186)?ASA,12mg/kg/d;

DIP,3.0mg/kg/d82016

NotprovidedASA,10mg/kg/d;DIP,3mg/kg/dASA,5–6mg/kg/d;DIP,6mg/kg/d

10?19yr1–20yr

VariousVarious

Borkonetal477/1986LeBlancetal117/1992Bradleyetal478/1997

VVIII

3wk–17yr1–17yr3–16yr

VariousVariousSt.Jude

*ASA?acetylsalicylicacid;DIP?dipyridamole;CVA?cerebralvascularaccident.SeeTable8forotherabbreviationsnotusedinthetext.ReproducedwithpermissionofMichelsonetal.3?Nohemorrhage.

?Thenumberofpatientstreatedwithantiplateletagentscouldnotbedetermined.(186)referstotheentirepatientpopulationofthestudy.116§Thedeathwassecondarytoamitralvalvethrombosis.

Incidence

Intheabsenceofprophylacticanticoagulationtherapy,theincidenceofsymptomaticTEsfollowingCCviathefemoralarteryisapproximately40%.302Youngerchildren(ie,those?10yearsofage)haveanincreasedincidencecomparedtoolderchildren.302Themostsignificantfactorinreducingtheincidenceistheuseofprophylacticanticoagulationtherapy,whichisdiscussedsubsequently.OtherparametersthatinfluencetheincidenceofTEincludeballoondilations,repeatedcathetermanipula-tions,andincreasedhematocrit.302–305Arterialcomplica-tionsfollowingCCaresixtimesmorelikelytooccurwhenballoonangiographyorvalvotomyisperformed.Aninten-tionalarterial“tear”iscreatedduringtheinsertionofballooncatheters,andthrombiformtooccludetheopen-ingonremovalofcatheters.Thelargesizeandirregularbumpysurfaceoftheballoonsmaycontributetoincreasedintimaltrauma,maycausespasms,andmayresultinTEs.306Patientsize,hemodynamicstatus,technique,andtotaltimeofarterialcannulationallplayinterconnectingrolesintheriskofTEs.307Theuseoflargercatheters(ie,largerFrenchsizes)isalsoassociatedwithahighinci-denceoffemoralarteryTEs.

Outcomes

OutcomesrelatedtoTEsfollowingCCcanbeconsid-eredasshort-termandlong-termconsequences.Short-termconsequencesofCCrelatedTEsincludethreatenedlimbviabilityandthemorbidityofinterventionwithanticoagulantsorthrombolytictherapy.Long-termconse-www.chestjournal.org

quencesoffemoralarteryTEslikelyreflecttheeffective-nessoftheinitialtherapyandincludeleglengthdiscrep-ancies,musclewasting,claudication,andlossofarterialaccess,whichisimportantforchildrenwhorequiremul-tipleCCs.308IfthereareadditionalTEsoftheprofundafemoralartery,claudicationandshortnessmightalsooccurinthethigh.Symptomaticischemiaismorelikelyduringrapidgrowth,suchasoccursinthefirstyearoflifeandduringpuberty.308

Latecomplicationsoffemoralarterycatheterizationcanbeclinicallyimportant.InastudybyTayloretal,30958childrenwhowere?5yearsoldatthetimeofcatheter-izationwereevaluated5to14yearslaterusingarterialduplexscanningandlowerextremityradiographsofbonelength.Arterialocclusionwaspresentin33%ofpa-tients.309Themeanankle/brachialindexinthecatheter-izedlimbswas0.79,andleggrowthretardationwaspresentin8%ofchildren.InastudybyCelermajeretal,310?30%ofpreviouslycatheterizedchildrenandado-lescentspresentedwithvascularaccessproblemsatsub-sequentcatheterizationsduetoanoccludedvessel,astenosedvessel,orscartissue.Thepracticalimplicationsofdifficultaccessincludeprolongedaccesstime,pro-longedtotalcatheterduration,andsignificantdiscomfortforpatientsstudiedunderlocalanesthesia.InastudybyHurwitzetal,311recatheterizationwasperformedin48children,6monthsto9yearsfollowingtheinitialstudy.Therewascompleteocclusionofthefemoralarteryin4of48patients(8%),withextensivehypogastriccollateraliza-tionreconstitutingthefemoralarteryapproximately3to4cmbelowtheinguinalligament.311

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Table10—ThromboembolicandHemorrhagicComplicationsofMechanicalProstheticHeartValvesTreatedWith

OralAnticoagulants*

Study/Year

Spevaketal479/1986

elMakhloufetal115/1987Haradaetal480/1990

LevelVVV

No.568340

Ages?5yr2–16yr4mo–15yr

ValveTypeVariousVariousSt.Jude

PositionAo,MAo,MAoMAo,M,?2valves

AoMAoM?2valvesAo,MAoM?2valves

AoMAoMPulmMAoM?2valvesAo,M,?2valvesAo,?2

TE,%pt-yr1.62.3NR1.32.30NR00.74.01.40.130.382.13.25.05.32.0NR1.1NR30.80.51.71.800.3

HEM,%pt-yr0.800NR0.5NR8.2000002.13.22.6NRNR0000NRNRNR0.900.3

1?Deaths4?1?

Stewartetal481/1987Bradleyetal476/1985Milanoetal482/1986

VVV

302071

6–17yr?19yr15yr

VariousVariousVarious

Schafferetal483/1987Solymaretal116/1991

VV

33(186)§

9–48mo1–20yr

St.JudeVarious

1?

Schaffetal484/1984V486mo–18yr

Starr-EdwardsSt.Jude

Borkonetal477/1986V223wk–17yr

Humanetal485/1982Antunesetal486/1989VV563522–12yr20yrVariousVarious

Woodsetal487/1986Champsauretal300/1997

VV

20?54

5mo–16yr1–17yr

VariousVarious

11HEM1TE1HEM1TE

Bradleyetal478/1997III486mo–18yrSt.JudeAo,M2.61.5

*SeeTables8and9forabbreviationsnotusedinthetext.Pulm?pulmonary.ReproducedwithpermissionofMichelsonetal.3?Thetypeofanticoagulantcouldnotbedetermined.?Deathwassecondarytoamitralvalvethrombosis.§(186)referstotheentirepopulationofthestudy.

?PatientsweretreatedwithacombinationofwarfarinandASA.

Prophylaxis

Therehavebeenfiveprospectivetrialsexaminingthevalueofprophylaxistopreventfemoralarterythrom-bosis(Table11).179,302,303,305,312Prophylacticanticoagu-lationtherapywithaspirindoesnotsignificantlyreducetheincidenceofarterialTEs.179However,anticoagula-tiontherapywith100to150U/kgheparinreducestheincidencefrom40to8%.302Althoughamorerecentsmallrandomizedtrialhassuggestedthata50U/kgbolusofheparinmaybeasefficaciousas100U/kgwhengivenimmediatelyafterarterialpuncture,thisstudywasunderpowered,andabolusof50U/kgcannotnotberecommendedasoptimalprophylaxisatthistime.305Recentadvancesininterventionalcatheterizationhaveresultedintheuseoflargercathetersandsheaths,whichmayincreasetheriskofTEs.Furtherheparin

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bolusesarefrequentlyusedinprolongedprocedures(ie,?60min),especiallyduringinterventionalcath-eterizations,however,thebenefitsofthispracticearenotknown.

Recommendations

1.14.1.ForneonatesandchildrenrequiringCCviaanartery,werecommendIVheparinprophylaxis(Grade1A).

1.14.2.Wesuggesttheuseofheparindosesof100to150U/kgasabolus.Furtherdosesmayberequiredinprolongedprocedures(bothGrade2B).

1.14.3.ForprophylaxisforCC,werecommendagainstaspirintherapy(Grade1B).

SeventhACCPConferenceonAntithromboticandThrombolyticTherapy

Table11—ThromboprophylaxisforCC*

Study/YearFreedetal302a/1974

Freedetal302/1974

Raoetal303/1981Girodetal312/1982

DesignRCTRCTRCTC

InterventionAspirin,15mg/kg;placebo

UFH,1mg/kg;placebo

UFH,100U/mL;placebo

UFH,100U/kgbolus;UFH,150U/kg?20U/kg/h;UFH,200U/kg?20U/kg/h

UFH,50U/kg;UFH,100U/kg

No.Outcome,%375840375660694381241

22248?411117110

theuseofthrombolytictherapyinchildrenwithafemoralarteryTEfollowingCC.SK,UK,andtPAhaveallbeenusedtotreatfemoralarteryTEsinchildren.131,307,313–318Ingeneral,thetreatmentoffemoralarteryTEsisusuallyeffectiveinpreventingtissueischemia,claudication,oramputation.

Embolectomy

Ingeneral,embolectomyshouldbeavoidedinsmallchildrenifthrombolytictherapyisnotcontraindicatedbecauseoftherisksofreocclusion.Foraballoonembo-lectomy,acatheterofappropriatesizeisintroducedthroughthepreviousarteriotomysiteandthenpassedretrogradelythroughthethrombus,upandintotheexternalandcommoniliacartery.Theballoonisinflated,andthecatheterisgentlywithdrawn.Completeevacua-tionoftheclotisusuallysignaledbyapulsatinggushofblood.Ifthatdoesnothappen,theprocedureisrepeated.Adistalclotindiscontinuityalsomaybepresent.Inthesepatients,thecatheterispasseddownthesuperficialfemoralartery,theballoonisinflated,andthecatheteriswithdrawn.Whengoodretrogradeandarterogradearte-rialbloodflowisachieved,thearteriotomyisclosed.319,320Embolectomyshouldbefollowedbyanticoagulantther-apytopreventreocclusion.

Saxenaetal305/1997

RCT

183183109

*C?cohort.ReproducedwithpermissionofMichelsonetal.3?p?0.05.

1.15FemoralarterythrombosisfollowingCC

Treatment

OptionsforthetreatmentofanacutearterialTEfollowingCCconsistofanticoagulanttherapy,thrombo-lytictherapy,embolectomy,andreconstructivesurgery.

Anticoagulants

Thegeneralpracticeinthemajorityofchildren’shospitalsistoinitiatetherapywithUFH.Previousstudieshavereportedthatapproximately70%ofTEswillresolveusingUFHalone,withoutexposingchildrentothegreaterrisksofthrombolytictherapy,embolectomy,and/orsurgi-calreconstruction.307DependingonthetimeintervalfromUFHadministrationduringCC,UFHisinitiatedwitheitherabolus,orasacontinuousinfusion.

Reconstructivesurgery

Theoptionsforreconstructivesurgeryincludethrom-bectomywithautogenoussaphenousveinpatchangio-plasty,directangioplasty,segmentalresectionwithend-to-endanastomosis,andinterpositionbypassgrafting.321Themainindicationforreconstructivesurgeryisclinicallysignificantclaudication,whichisinevitablyaccompaniedbyshorteningofthelimband/ormusclewasting.Inmostcases,Dopplerultrasoundandangiogramviathecon-tralateralfemoralarteryarerequiredtoestablishthevascularanatomy.Reconstructivesurgeryofanischemicbutviablelimbinasmallchildisprobablybestdeferredifpossiblebecausefuturedefinitivesurgeryinlargervesselsismorelikelytobesuccessful.

Thrombolytictherapy

Ifthearterialocclusiondoesnotresolve,thrombolytictherapyisusuallypreferredoverembolectomybecauseofthepooroutcomeofembolectomyinverysmallchil-dren.307Table12summarizestheavailableinformationon

Table12—ThrombolyticTherapyforFemoralArteryThrombosisDuetoCC

SuccessfulOutcome,

%871001001001005894100

Study/Year

Wesseletal313/1986Inoetal307/1988KirkandQureshi314/1989Brusetal315/1990Kotharietal316/1996Levyetal317/1991Zenzetal131/1993Riesetal318/1994

AgentSKSKUKSKSKSKtPAtPAtPA

Age2d–40mo3d–55mo3d–34mo0.02–1.5yr1–9mo1d–17yr2d–47mo14–53mo

No.16111491212176

InfusionDose1,000U/mL1–2,000U/mL4,000U/mL750–1,000U/mL1–2,000U/mL1,000U/mL0.1–0.5mg0.5–0.25mg0.5mg

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Recommendations

1.15.1.Forchildrenorneonateswithafemoralarterythrombosis,werecommendtherapeuticdosesofIVhep-arin(Grade1C).Wesuggesttreatmentforatleast5to7days(Grade2C).

Remark:Theoptimaldurationoftherapyisunknown.1.15.2.Forchildrenorneonateswithlimb-threateningororgan-threatening(viaproximalextension)femoralarterythrombosiswhofailtorespondtoinitialheparintherapy,andwhohavenoknowncontraindications,werecommendtheadministrationofthrombolytictherapy(Grade1C).

1.15.3.Forchildren,inselectedcasesoffemoralarterythrombosis,wesuggestsurgicalintervention,inparticularwhenthereisacontraindicationtothrombolytictherapy,orwhenorganorlimbdeathisimminent(Grade2C).1.16Peripheralarterythrombosis

Prophylaxis

Theincidenceofperipheralarterycatheter-relatedTEsinchildrenwasreportedinthreestudies,304,322,323someofwhichalsoassessedtheroleofspecificinterventionstomaintaincatheterpatency.Buttetal304assessedinfusionflowratesof2and1mL/hin319patients,andreportedthattherewasnosignificantdifferenceinthedurationofcatheterpatency.However,increasingtheconcentrationofheparinfrom1to5U/mL(154patients)significantlyprolongedcatheterpatency.304Selldenetal322assessedintermittentflushingvscontinuousflushingwithheparin-containingsolutionsin338patientswhowere?1yearofageandhadradialarterialcatheters.Catheterswereremovedduetomalfunctionin76%ofpatientsreceivingintermittentflushescomparedto52%ofpatientsreceiv-ingcontinuousinfusionsofheparin.322Inarandomizedcontrolledtrial(RCT),Rais-Bahramietal323evaluatedprematurecatheterremovalin60newbornswithperiph-eralarterialcatheters.Thepatencyofperipheralarterialcatheterswasprolongedininfantsreceivingheparin-normalsalinesolutionflushescomparedtothosereceivingheparin-dextroseflushes.323Heulittetal324comparedsolutionscontainingornotcontainingpapaverinein239children,aged3weeksto18years.Ninety-threeper-centofcathetersflushedwithpapaverine-supplementedsolutionswerepatentcomparedto78%ofcathetersnotflushedwithpapaverine-supplementedsolutions.324Tarryetal326identified44casesofperipheralarterialTEssecondarytocatheterizationsinchildrenwithnephroticsyndrome.Ofthesepatients,TEswerecausedbyvesseltraumasecondarytoattemptedbloodsamplinginninecases(20%).326

Clinicalpresentationanddiagnosis

Carefulmonitoringoftemperature,color,andcapillaryrefilltimeofthehandorfootisimportantfortheearlydetectionofarterialcatheter-relatedTEs.TEsintheradialarteryusuallydonotresultinthelossoftheentire

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hand,unlesstheulnararteryisabsent.Acuteimpairmentofarterialbloodflowtothehandorfootischaracterizedbydiminishedorabsentpulses,aprolongedcapillaryrefilltime,andacool,palehandorfoot.DopplerultrasoundisusuallyusedtoprovideconfirmationofthepresenceofaTE.

Recommendations

1.16.1.Forneonatesandchildrenwithperipheralarte-rialcathetersinsitu,werecommendtheadministrationoflow-doseheparinthroughthecatheter,preferablybycontinuousinfusion,toprolongthecatheterpatency(Grade1A).

1.16.2.Forchildrenwithaperipheralarterialcatheter-relatedTE,wesuggesttheimmediateremovalofthecatheter(Grade2C).Wesuggestsubsequentanticoagu-lationtherapywithorwithoutthrombolysis,dependingontheclinicalsituation(Grade2C).

1.17PositioningofumbilicalarterialcathetersIngeneral,positionsareconsideredas“high”withumbilicalarterialcatheter(UAC)tipsbetweenT6andT10,and“low”withUACtipsbetweenL3andL5.HighUACshavebeenreported327–334tofunctionbetterwithfewercomplications.However,thecomplicationsmaybemoreserioussincealocalthrombusmayaffecttheceliac,mesenteric,andrenalarteries.TheclinicalrelevanceoftheseTEsisuncertain,andmajorarteryTEscanstilloccurwithUACsinalowposition.335–337InalargeretrospectivesurveyofUACpractices,338117physiciansresponded,with44%reportingtheuseofhighUACs,44%reportingtheuseoflowUACs,and12%havingnopreference.TherehavebeentwoRCTs334,339thatassessedtherelationshipbetweentheplacementoftheUACtip(ie,highorlow),andbothblockageandnecrotizingentero-colitis.TheUmbilicalArteryCatheterTrialStudyGroupreported334nosignificantdifferenceintheincidenceofnecrotizingenterocolitisorICHordeath,betweenthehighorlowplacementofUACs.Inarandomizedstudyof308patientswithUACsbyKempleyetal,339theincidenceofnecrotizingenterocolitiswasnotinfluencedbythehighorlowplacementofUACswithintheaorta.UACswithtipshighintheaortawereinplaceforlongerperiodsoftimecomparedtoUACslowintheaorta,whichwerealsoassociatedwithanincreasedrateoflowerlimbblanchingandcyanosis.339Atthistime,thereisnoconvincingevidencethatthelocationofthetipofUACsinfluencestheincidenceofTEs.327,338–342

1.18Aorticthrombosissecondarytoumbilicalar-terycathetersinneonates

Arterialaccessinsickprematurenewbornsisneces-saryforbloodgasanalysesandthecontinuousmonitor-ingofoxygensaturationandBP,andtofacilitaterepetitivebloodsampling.Theumbilicalarteryisthemostcommonsitechosenfornewbornsbecauseofthesizeandeaseofaccess.ComplicationsofUACplace-mentincludeTEs,vasospasm,bleeding,infection,and/orhypertension.343,344

SeventhACCPConferenceonAntithromboticandThrombolyticTherapy

TheclinicalpresentationofUAC-relatedTEsvariesdependingontheextentofthethrombosisandtheinvolvementofotherarteries.Themajorityofinfantsareclinicallyasymptomaticorhaveminorsymptoms,whileasmallerpercentageofpatientshavemajorsymptomsofsevereischemiatothelegsandselectedorgandysfunction.TEsassociatedwithUACsmaycausenecrotizngentero-colitissecondarytomesentericarteryocclusion,emboliceventstothelowerlimbsandemboliceventstotheCNSviaaright-to-leftshunt,suchasapatentforamenovale.TheincidenceofmajorclinicalsymptomssecondarytoUACsoccurinapproximately1to3%ofinfants.341,345–349The“goldstandard”testforthediagnosesofUAC-relatedTEsiscontrastangiography,11whichis,unfortunately,rarelyfeasible.Alowindexofsuspicionisindicated,asevidencedbyadisturbinglylargeproportionofaorticTEsdiagnosedatautopsy.11,350,351Noninvasiveimagingtech-niquessuchasDopplerultrasoundareattractivebecauseoftheireaseofperformanceatthebedside.However,thevalidityofthesetechniqueshasnotbeenestablished.Theneedtocriticallyassessthesediagnostictestswasillus-tratedinastudy12inwhichreal-timeultrasoundfailedtovisualizeaorticTEsinfourpatients,threeofwhomhadcompleteaorticobstructiondetectedbycontrastangiog-raphy.

TherearenocomparativedatatodeterminetheoptimaltreatmentforanaorticthrombosissecondarytoaUAC,andanticoagulation,thrombolysis,andthrom-bectomyhaveallbeenreported.Thedegreeofurgencyfortreatmentincreasesifthereisevidenceofrenalimpairment,asdialysisisusuallynottechnicallypossi-bleinneonates,andacuterenalfailureisthereforefatal.

Alow-dosecontinuousheparininfusion(1to5U/h)iscommonlyusedtomaintaincatheterpatency.Theeffec-tivenessofheparinwasassessedinonelargetrial349andfivesmallerrandomizedtrials.352–356Thefollowingthreeoutcomeswereassessed:patency;localthrombus;andICH.Patency,whichislikelylinkedtothepresenceofalocalthrombus,isprolongedbytheuseoflow-doseheparin.352,354–357Theincidenceoflocalthrombus,de-tectedbyultrasound,wasnotdecreasedintworandom-izedstudies.However,thepowerofbothstudieswaslow.349,355ICHasanoutcomewasnotincreasedintworandomizedstudies.However,thesamplesizeinonestudywassmall(15patientsperstudyarm).356Intheotherstudy,358theoddsratioforICHandheparinusewas1.49(95%CI,0.62to3.59).Intwocohortstudies,342,359,360heparintherapywasimplicatedasariskfactorforICHinlow-birth-weightinfants.Onestudy359wasretrospective,withthe95%CI(1.4to11.0)aroundtheoddsratioof3.9beinglargeandthemagnitudeoftheriskuncertain.Althoughthesecondstudy342reportedapositivecorrela-tionbetweenheparindoseandthefrequencyofICH,theseverityofillnesswasalsopositivelycorrelatedwithheparindose,andtheeffectscouldnotbedifferentiated.Largewell-designedstudiesarerequiredtodeterminewhetherlow-doseheparininfusionaffectstheincidenceofICH.

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Recommendations

1.18.1.ForUAC,wesuggestprophylaxiswithlow-doseheparininfusion(1to5U/h)[Grade2A].

1.18.2.WesuggestthataorticthrombosissecondarytoaUACismanagedbythesameprinciplesasfemoralarterythrombosissecondarytocardiaccatheters.Ifthereisevidenceofrenalfailure,thenurgentrestorationofrenalbloodflowisrequired,andwesuggestthrombolysisorthrombectomy(allGrade2C).

1.19SpontaneousaorticthrombosisinneonatesSpontaneousaorticthrombosisinneonatesisanun-commoneventofunknownetiology.Theclinicalpresen-tationoftenmimicsseverecoarctation,complicatedbyorganischemia.Treatmentoptionsincludethrombec-tomy,thrombolytictherapy,andanticoagulationtherapywithheparinorLMWH.Thereisahighmortalityrateirrespectiveoftherapy,oftenduetoacuterenalfailure.Theoptimaltherapydependsontheavailabilityofsurgicalexpertise,theassociatedriskfactorsforbleeding,andthedegreeoforganischemia(ie,thecriticaltimeavailablefortherapytobesuccessful).Therapyshouldbeindividual-izedbasedonthesefactors.215,361–366

Recommendation

1.19.1.Forchildrenexperiencingspontaneousaorticthrombosiswithevidenceofrenalischemia,wesuggesttheurgent,aggressiveuseofthrombolyticorsurgicaltherapy,supportedbyanticoagulationtherapywithhepa-rinorLMWH(Grade2C).1.20Kawasakidisease

In1967aJapanesepediatrician,TomisakuKawasaki,described50childrenwhohadfeverfor?5days,rash,bilateralnonexudativeconjunctivitis,inflammationoftheoralmucosa,erythema,swellingofthehandsandfeet,andcervicaladenitis.Duringtheacutephase,Kawasakidis-easemaycausemedium-vesselandlarge-vesselarteritis,arterialaneurysms,valvulitis,andmyocarditis.Ofparticu-larconcernarecoronaryarteryaneurysms,whichmaystenoseorthrombose.Theincidenceofcoronaryarteryaneurysmsintheabsenceofinitialtreatmentisapproxi-mately20to25%.367Coronaryarterialaneurysms,orextasia,mayleadtomyocardialinfarction,suddendeath,orchroniccoronaryarterialinsufficiency.367KawasakidiseaseistheleadingcauseofacquiredheartdiseaseinchildreninNorthAmerica.

InpatientswithKawasakidisease,aspirinisinitiallygiveninhighdoses(80to100mg/kg/dduringtheacutephase,forupto14days)asananti-inflammatoryagent,theninlowerdosesasanantiplateletagent(3to5mg/kg/dfor?7weeks)topreventcoronaryaneurysmthrombosisandsubsequentinfarction(themajorcauseofdeathinpatientswithKawasakidisease).Earlycohortstudies368,369suggestedthataspirinreducedthecoronaryinvolve-mentinpatientswithKawasakidisease.Aninitialmeta-analysis367concludedthatchildrentreatedwithIVgam-CHEST/126/3/SEPTEMBER,2004SUPPLEMENT

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maglobulinandaspirinhadasignificantlylowerincidenceofcoronaryarteryaneurysmsthanthosetreatedwithaspirinalone.Muchofthetreatmentdifferenceinthisanalysiswasduetoonerandomizedstudy369thatdemon-stratedthatthecombinationofIVgammaglobulinandaspirinismoreefficaciousinthisregardthanaspirinalone.TherearenowmanyrandomizedtrialsofIVgammaglobu-lininKawasakidisease.Arecentmeta-analysis360ofrandomizedtrialsofIVgammaglobulin,concludedthatchildrenfulfillingthediagnosticcriteriaforKawasakidiseaseshouldbetreatedwithIVgammaglobulin(2g/kgsingledose)within10daysoftheonsetofsymptoms.Inonestudy,123childrenwithKawasakidiseasewhoweretreatedwiththeGPIIb-IIIaantagonistabciximab,inadditiontostandardtherapy,demonstratedgreaterregres-sionincoronaryaneurysmdiameteratearlyfollow-upthandidpatientswhoreceivedstandardtherapyalone.

Recommendations:ChildrenWithKawasakiDisease

1.20.1.Werecommendtherapywithaspirininhighdoses(ie,80to100mg/kg/dduringtheacutephase,forupto14days)asananti-inflammatoryagent,theninlowerdoses(ie,3to5mg/kg/dfor7weeksorlonger)asanantiplateletagent(Grade1C?).

1.20.2.WerecommendtherapywithIVgammaglobulin(2g/kg,singledose)within10daysoftheonsetofsymptoms(Grade1A).

1.21AnticoagulationtherapyforKawasakidiseasechildrenwithgiantaneurysms

TherearenoformalstudiescomparingtherapyforchildrenwithgiantcoronaryarteryaneurysmssecondarytoKawasakidisease.Long-termwarfarintherapyiscom-monlyused,withatargetINRof2to3.Theefficacyandsafetyofthistherapyremainsunknown.

Recommendation

1.21.1.Inchildrenwithgiantcoronaryaneurysmsfol-lowingKawasakidisease,wesuggesttherapywithwarfarin(targetINR,2.5;INRrange,2.0to3.0)inadditiontotherapywithlow-doseaspirin(Grade2C).1.22Sinovenousthrombosisinneonates

TheCanadianPediatricIschemicStrokeRegistry10reported180childrenwithsinovenousthrombosis(SVT).Newbornscomprised43%ofchildrenyieldingaminimumincidenceof41per100,000newbornsperyear.428TheavailableinformationsuggestedthatSVTisunderdiag-nosedinnewborns,inparticularinassociationwithas-phyxia370orseizures.371

Intheneonatalperiod,thebrainisstillrelativelyimmature.Asaresult,newbornswithcerebraldamagemanifestonlyalimitednumberofclinicalsigns.Innewborns,themostfrequentneurologicsignsofSVTareseizures,whicharepresentin?70%,andlethargy.Hemiparesisispresentin?10%ofnewborns.10Innew-668S

bornswithextensiveSVT,externalsignsmayincludeatenseanteriorfontanelle,theseparationofbonysuturesreflectingintracranialhypertension,anddilatedscalpveins.Followingtheinitialdiagnosis,thepropagationofthethrombosismayoccurintheabsenceofclinicaldeterioration.164

TheriskfactorsforneonatalSVTcanbeconsideredasphysiologicfactorsthatmaypromoteSVT,pathologicfactorsthatareassociatedwiththebirthprocess,orpostnataldiseases.Duringbirth,thenormalmoldingandoverlappingofthecranialsuturescandamagethecerebralsinusstructuresthatimmediatelyunderliethesagittalandlateralsinuses,provokingthrombosis.372Inthepostnatalperiod,venousflowwithinsinusesisalteredbyheadpositioning.373Perinatalcomplicationsincludingasphyxiaarepresentin24%ofneonateswithSVT.Asphyxiacanitselfproduceseizuresandlethargy,creatingdiagnosticconfusionbetweenSVTandasphyxia.However,SVThasbeenfrequentlyfoundwithcerebralangiographyper-formedinseverelyasphyxiatedneonates.374NewbornillnessesthatincreasetheriskforSVTincludedehydra-tion,sepsis,andheadandneckdisorders,includingmen-ingitisandothers.

ThemostfrequentlyinvolvedsinusesinneonatalSVTarethesuperiorsagittalandlateralsinuses,whicharethemajorcomponentsofthe“superficial”sinussystem.Cor-ticalveinthrombosisisrare.The“deep”sinovenoussystem,includingtheveinofGalen,thestraightsinus,andtheinternalcerebralveins,ismuchlessfrequentlyin-volved.10CerebralparenchymallesionsareassociatedwithSVTinnearlyhalfofnewbornsandincludevenousinfarcts,whicharefrequentlyhemorrhagicand,insomenewborns,areassociatedwithtransientfocaledema.Sagittalsinusthrombosiscancauseacommunicatinghydrocephalusresultingfromtheimpairedabsorptionofcerebrospinalfluidintothearachnoidgranulationsthatlinethesagittalsinus,leadingtoincreasedintracranialpressure.

TheneurologicoutcomeofneonatalSVTisunclearintheliterature,eventhough?90%ofnewbornswithSVTsurvive.371Thebestavailableestimate375isthatafterameandurationof2.1years,77%ofnewbornssurvivingSVThavenoneurologicsequelae.However,giventhedelayedonsetofsignsofneurologicinjuryinnewborns,furtherlong-termfollow-upstudiesarerequired.Thecurrentdataindicatethatthepresenceofvenousinfarc-tionisassociatedwithapooroutcome.

AnticoagulanttherapyforneonatalSVTiscontroversialandislikelynotindicatedinthepresenceofalargeinfarctorsignificantCNShemorrhage.However,intheCanadianRegistryofSVT,overonethirdofnewbornswithSVTreceivedanticoagulantmedicationswithoutmajorbleed-ingorextensionoftheSVT.10Ifanticoagulantsarenotused,radiographicfollow-upforsubclinicalprogressionisimportantand,ifitoccurs,wouldusuallyresultintheneedfortherapywithanticoagulants.10,16,376

Recommendations

1.22.1.Forneonateswithcerebralvenousthrombosis,withoutlargeischemicinfarctionsorICH,wesuggest

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initialtreatmentwitheitherUFHorLMWH,followedbyLMWHtherapyfor3months(Grade2C).

1.22.2.Forneonateswithcerebralvenousthrombosis,withlargeischemicinfarctsorICH,wesuggestradio-graphicmonitoringandthecommencementofanticoagu-lationtherapyifextensionoccurs(Grade2C).1.23Sinovenousthrombosisinchildren

CerebralSVT(CSVT)isincreasinglyrecognizedinchildren.IntheCanadianPediatricRegistry,10thenon-neonatescomprised57%ofchildren,yieldingaminimumincidenceof0.25per100,000olderinfantsandchildrenperyear.

TheclinicalfeaturesofchildhoodCSVTaresubtle,diffuse,anddominatedbyseizures.Signsofraisedintra-cranialpressuretypicallydevelopgraduallyoverhours,days,orevenweeks.Theclinicalpresentationisinflu-encedbytheageofthechild,theextentandlocationofthethrombus,andthepresenceorabsenceofassociatedvenousinfarction.

Diffuseneurologicsignsandsymptoms,suchashead-aches,adecreasedlevelofconsciousness,andpapilloe-dema,arepresentin90%ofthepatients,andseizuresarepresentin48%.Hemiparesisispresentinonly17%ofpatients,10andhasbeenfoundin25%ofchildrenandadultswithpseudotumorcerebriundergoingangiographyormagneticresonancevenography(MRV).377,378Visualdisturbances,includingdiplopia,increasedcentralsco-toma,orothervisualfielddeficitsarepresentin18%ofchildren.

InchildhoodCSVT,thrombosisresultsfromacombi-nationofintravascularandvascularfactors.Underlyingriskfactors,includingprothromboticstates,may“predis-pose”thepatienttothrombosis,whileacuteillnessesorprothromboticmedicationsactastriggeringfactors.Only3%ofchildrenintheCanadianPediatricRegistryhad“idiopathic,”CSVTcomparedwithanestimated10to25%ofadults.379Pregnancy,380malignancy,381,382anduseofexogenoussteroids,whicharefrequentlyassociatedwithCSVTinadults,areonlyrarelyfoundinchildrenwithCSVT.383

Headandneckinfectionsresultingin“septic”CSVTareparticularlycommoninpreschoolchildrenrelatedtootitismediaandmastoiditis.10Acuteillnesses,includingsepsisordehydration,arepresentinnearlyonethirdofchildrenwithCSVT.Headtraumaorcranialsurgerymaydamageduralsinuses,triggeringCSVT.Chronicsystemicdiseases,includingsystemiclupuserythematosus,nephroticsyn-drome,inflammatoryboweldisease,hematologicdisor-ders,cardiacdisease,andothers,areanunderlyingriskfactorin60%ofthepatients.10,384,385Inolderinfants,irondeficiencyanemiamaybeassociatedwithCSVT.386

Therearefrequentlymultiplesitesofobstructionwithinthecerebralsinovenousstructuresinchildrenatthetimeofdiagnosis.Themostfrequentlyinvolvedarethelateralsinuses(includingthetransverseandsigmoidsinuses)andthesuperiorsagittalsinus,themajorcompo-nentsofthesuperficialsinussystem.Corticalveinthrom-bosisispresentin9%ofpatients.Thedeepsinovenoussystem,includingtheveinofGalen,thestraightsinus,and

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theinternalcerebralveins,isinvolvedin36%ofpatients.Jugularveinsareinvolvedin14%patients.CavernoussinusthrombosishasbeenreportedinchildrenfromThailand387andIndia,388althoughitisrarelyreportedinNorthAmericanorEuropeanseries.Nearly41%ofchildrenwithCSVThaveassociatedparenchymalinfarcts.IntheCanadianPediatricRegistry,10thesewerehemor-rhagicin57%.

Themajorityofchildren(90%)withCSVTsurvivetheinitialillness.DeathsareattributabletotheCSVTinapproximatelyonequarterofpatientswhodie.IntheCanadianPediatricRegistry,10outcomeswereassessedin82olderinfantsandchildrenatameanintervalfromthrombosistothelastfollow-upvisitof1.6years(range,0.05to5.2).Therewere42patients(51%)withnormaloutcomes,32(39%)withneurologicdeficits,and8(10%)whodied,2asaconsequenceoftheCSVT.OtheroutcomesintheCanadianPediatricRegistryincludedseizuresin11%ofpatientsandrecurrentTEsin17%.PredictorsofadverseneurologicoutcomeordeathintheCanadianPediatricRegistryincludedseizuresatonsetandthepresenceofavenousinfarct.Althoughneurologicdeficitsarepresentinnearlyhalfofpatients,deficitsimpactingonneurologicfunctionoccurinabout20%.375Thelong-termfollow-upofaffectedchildrenisveryimportantsincetheonsetofsignsofneurologicinjuryisdelayedinthisagegroup.

IntheabsenceofmajorCNShemorrhage,anticoagu-lationtherapyisappropriate.Anticoagulationtherapyisadministeredfor3monthsiffullrecanalizationisseenonthe3-monthmonitoringCTscan/MRVexamination,orfor6monthsifonlypartialrecanalizationisseenonthe3-monthmonitoringCT/MRVexamination.Asimilardoseintensitytothatdescribedforthetreatmentofnon-CNSvenousthrombosis(targetINR,2.0to3.0)isutilized.The6-monthtreatmentdurationisconsistentwiththetreat-mentapproachforadultCSVT.Smallpetechialorlocal-izedhemorrhageconfinedtoanareaofvenousinfarctionmaynotbeacontraindicationtoanticoagulationtherapy.Ifnoanticoagulantsareadministered(eg,significanthem-orrhage)repeatMRVorCTvenographyshouldbeob-tainedat1weekafterdiagnosistoassessforpropagationoftheinitialthrombosis.389–391

Recommendation

1.23.1.ForchildrenwithCSVT,wesuggesttreatmentfor5to7dayswitheitherUFHorLMWHfollowedbyLMWHorVKAs(targetINR,2.5;INRrange,2.0to3.0)for3to6monthseveninthepresenceofalocalizedhemorrhagicinfarct(Grade2C).

1.24Arterialischemicstrokeinneonates

Incidence

Newbornscomprise25%ofchildrenwitharterialisch-emicstroke(AIS).375PreviousestimatesoftheincidenceofneonatalAIShavebeen28.6per100,000livebirths.410IntheCanadianPediatricRegistry,412theincidenceofAISinnewbornsis93per100,000livebirths.

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Clinicalfeatures

NewbornswithAIStypicallypresentwithseizuresorlethargyduringthefirstfewdaysoflife.Insystematicstudies393,394ofnewbornswithseizures,12to14%havebeenfoundtohavecerebralinfarctions.Focalsignsarerare,withhemiparesispresentin?25%ofnewborns.395Insomenewbornswithanormalneonatalcourse,hemi-paresisisfirstdetectedduringlaterinfancy(typically,between4and8monthsofage)leadingtoaCTscan,whichdemonstratesthefindingsofaremotecerebralinfarct(presumedtohaveoccurredprenatallyorperina-tally).Insuchinfants,theAISispresumedtohaveoccurredinutero,orintheperinatalperiodwithnooronlysubtlesignsatbirth.TheimportantimplicationisthatAISisneverdiagnosedininfantswithpresumedprenatalorperinatalstrokewhohaveonlymildornoneurologicsequelae.Thenumberofchildrencomprisingthelattergroupisunknown.411,413

Radiographicfeatures

Innewborns,arterialinfarctsoccurslightlymoreofteninthelefthemispherecomparedwiththerighthemi-sphere.Overtwothirdsofnewbornshavelarge-vesselinfarcts,withtheremainderhavingsmall-vesselinfarcts,whichisincontrasttothesituationinolderinfantsandchildreninwhomnearlyhalfhavesmall-vesselinfarcts.Thecarotid(anterior)circulationisfivetimesmorelikelytobeinvolvedinneonatalstrokecomparedwiththeposteriorterritory.NeonatalAISsarehemorrhagicin20%ofpatients,andmultipleinfarctsarepresentin15to20%.392

Riskfactors

AprimaryriskfactorforAISisdefinableinapproxi-matelytwothirdsofaffectednewborns.411,412Systemicriskfactorsarepresentinoverhalfofnewborns,andincludecardiacdisease(10%),perinatalcomplications(50%),396otheracuteillnessesincludingdehydration,andprothrom-boticdisorders(25to68%).163,411,412CongenitalPCdefi-ciency,PSdeficiency,factorVLeidenmutation,andincreasedlipoproteinAlevelshaveallbeenreportedinnewbornsandchildrenwithperinatalinfarction.163,398,402–405Acquiredconditionsaremorefrequent,andincludethepresenceofantiphospholipidantibodies(ie,anticar-diolipinantibodiesandlupusanticoagulant)406,407andacquireddeficienciesofPC,PS,AT,andactivatedPCresistance.170

Outcome

ThemortalityratefollowingAISinnewbornsis?10%.Neurologicdeficitsaredetectedintwothirdsofsurvivorsbyseveralyearsofage.408Lesionsthatinvolvethemotorcortex,internalcapsule,andbasalgangliatogetherareassociatedwithincreasedmotordisabilitycomparedwithlesionslimitedtothecortexorbasalgangliaalone.409,412,413Otherpredictorsofoutcomeremaintobedefined.Inonethirdofnewborns,theoutcomeisnormal.375However,

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seizuredisordersarepresentinthelongterminupto15%of?cerebral5%children.ofthrombosis.newbornsIncontrastwithAIStoolderhaveinfantsrecurrentandchildren,follow-upsystemicstudiesareor375Long-termneededtoelucidatetheextentofmoresubtleadverseoutcomes,includinglearningdisordersthatcannotbedetectedatyoungages.

Therehavebeennumeroustrials410–413inadultswithAISshowingthebenefitoftherapywithaspirinand,inspecificsubpopulations,therapywithtPA,UFH,orLMWHandVKAs.InnewbornswithAIS,thrombolytictherapyisrarelyifeveranoption.Anticoagulantandantiplatelettherapyarecontroversial.SimilartotherapyforSVT,anticoagulanttherapyislikelynottobeindicatedinthepresenceofalargeinfarctorsignificantCNShemorrhage.IntheCanadianRegistryofAIS,?10%ofnewbornsreceivedanticoagulantmedication.375WhentheetiologyoftheAISisclearlyembolic,anticoagulantther-apyshouldbeseriouslyconsidered,evenifthecommence-mentoftherapyisdelayed.

Recommendations

1.24.1.ForneonateswithnoncardioembolicAIS,wesuggestthatcliniciansdonotuseanticoagulationoraspirin(Grade2C).

1.24.2.ForneonateswithcardioembolicAIS,wesug-gestanticoagulationtherapywitheitherUFHorLMWHfor3months(Grade2C).

1.25Arterialischemicstrokeinchildren

Thediagnosisandtreatmentofchildrenwithstrokedifferfromthoseinadultsandarefrequentlyproblem-atic.First,strokeiscommoninadults,whichresultsinrapidrecognitionandthepotentialforearlyinterven-tion.414Strokeinchildrenisveryrare,withreportedincidencesof0.063to0.12per10,000childrenperyearandanAIS/SVTratioof3:1.408,415,416Theinfrequencyofstrokeinchildrenresultsindelayedrecognitionandaninabilitytointerveneearlywithmedicationsthatmayreducesubsequentneurologicdeficits.Althoughrare,theincidenceofstrokeinchildrenissimilartotheincidenceofbraintumors,forwhichacoordinatedresearchapproachhassignificantlydecreasedthemor-talityandmorbidity.Second,vascularocclusivestrokesinadultsaresecondarytoatheroscleroticdiseaseinthevastmajorityofpatients,whichpermitsatargetedapproachtothediagnosis,prevention,andtreatmentofstroke.Incontrast,vascularocclusivestrokesinchil-drenaresecondarytoamultitudeofdiseasesthathinderthediagnosis,prevention,andtreatmentofstrokeinpediatricpatients.Third,therehavebeennumerouswell-designedstudiesinvestigatingprophy-lacticandtherapeuticoptionsforadultswithstroke.Therehavebeennowell-designedinterventiontrialsinchildren,mostlyreflectingalowincidenceandmulti-tudeofetiologies.

ThetypicalclinicalpresentationofAISintoddlersandolderchildrenisanacute,prolongedneurologicdeficitsuchashemiparesis,withorwithoutseizures.Seizuresat

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theonsetofstrokearerelativelyfrequentinchildrencomparedwithadults,417,418andonlyafteraprolongedpersistentfocaldeficitthatisinconsistentwithToddparesisisstrokeconsideredtobelikely.Dystoniaismorecommoninchildrenwithbasalgangliainfarctionthaninadults.419RiskfactorsinchildrenwithAISaredefinableinapproximately80%ofcases,397–403,420–423areage-related,anddiffersignificantlyfromadults.Embolicstrokesec-ondarytoCHDisthemostfrequentcauseofstrokeduringchildhood.396

MoyamoyadiseaseoccursprimarilyintheJapanesepopulation,andischaracterizedbyprogressivestenosisandocclusionofthecerebralarteriesattheCircleofWillis.Inresponsetothestenosis,anabnormalnetworkofsmallcollateralvesselsdevelops,creatingthechar-acteristic“puffofsmoke”appearanceonangiograms.ChildrenwithMoyamoyadiseasepresentwithrecur-renttransientischemicattacksaswellasAISs.Ingeneral,thereisaprogressiveneurologicdeteriorationthatischaracterizedbysignificantimpairmentofmotorandcognitivefunction.424Hemorrhage,althoughcom-moninadultswithMoyamoyadisease,isrelativelyrareinchildren.424–427NospecificmedicaltherapyhaltstheprogressionofMoyamoyadisease.MoyamoyasyndromeisadisorderwithasimilarangiographicappearancetoMoyamoyadiseasebutissecondarytoseveralslowlyprogressiveocclusivecerebralvasculopathies,suchassicklecelldiseaseorpostradiationvasculopathy.Al-thoughanticoagulanttherapyhasbeenusedtotreatchildrenwithMoyamoyadisease,theefficacyandsafetyhavenotbeendetermined.

ThetreatmentofAISduringchildhoodiscomprisedprimarilyofsupportivemeasuresthatarefocusedontheunderlyingdiseaseandtheuseofantithromboticagents.Supportivetherapyisnotdiscussedfurther,andreadersarereferredtoseveralreviews.428Theroleoftreatmentwithantithromboticagentsisuncertaininchildrenastherearenocontrolledtrialsassessingtherisk/benefitratioinchildrenwithdifferentformsofAIS.Ifantithrom-botictherapyisused,thecurrentguidelineshavebeenextrapolatedfromrecommendationsforadults,whichmaynotbeoptimalbutareuseful.429AntithrombotictherapyforadultswithAISincludesinitialtherapywithaspirinformostpatients,andlesscommonlywithUFHorLMWHand/orthrombolytictherapy,aswellasmaintenancether-apywitheitherantiplateletagentsorVKAsforsecondaryprevention.81

TheaccumulatingexperiencewithantithromboticandanticoagulanttreatmentinchildrensuggeststhattheseagentscanbesafelyusedinchildrenwithAIS,althoughtheirefficacyandproperdosestillneedtobeestablishedbyRCTs.TheuseofthrombolyticagentsinchildrenwithAIS,however,hasbeenrare,andtherisk/benefitratioisunknownatthistime.IfAISisassociatedwithhemor-rhage,hypertension,orotherrelativecontraindicationstoanticoagulanttherapy,anticoagulanttherapymaynotbefeasible.TherisksofrecurrenceortheprogressionofcerebralTEsshouldbebalancedagainsttherisksoftreatment,particularlybleeding.

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Recommendations

1.25.1.ForchildrenwithAIS,wesuggesttreatmentwithUFHorLMWHfor5to7daysanduntilcardioem-bolicstrokeorvasculardissectionhasbeenexcluded(Grade2C).

1.25.2ForchildrenwithAISandcardioembolicstrokeorvasculardissection,wesuggesttreatmentfor5to7dayswithUFHorLMWHfollowedbytherapywithLMWHorVKAsfor3to6months(Grade2C).

1.25.3.ForallchildrenwithAIS,wesuggesttreatmentwithaspirin,2to5mg/kg/d,afteranticoagulationtherapyhasbeendiscontinued(Grade2C).

Strokeinsicklecelldisease

Ischemicstrokeoccursinapproximately10%ofchil-drenwithsicklecelldiseaseandisasignificantcauseofmorbidity.430–435Ischemicstrokeisusuallyaresultoftheocclusionoflargeintracranialarteries,mostcommonlytheintracranialinternalcarotidartery,andproximalportionsofthemiddlecerebralandanteriorcerebralarteries.436Pathologically,thelesionsarecharacterizedbystenoticarteriallesionswithfibroticscars,possiblyfromincremen-talthrombusformationwiththeincorporationofsicklederythrocytes.437Theclinicalpresentationreflectsthesiteoftheocclusion.Hemorrhagicstrokeoftenoccurslaterandisusuallyrelatedtopreviousocclusivevasculopathyor,lesscommonly,arupturedaneurysm.438

Treatmentofischemicstroke

TheNationalInstitutesofHealthhaspublishedguide-lines439forthepreventionandmanagementofstrokeinchildren.Studies440haveconfirmedthevalueoftranscra-nialDopplerimagingtoscreenat-riskchildren.Whileinchildrenwithestablishedstroketherearenocontrolledtrialsthatdemonstratetheadvantageofexchangetrans-fusionoversimpletransfusion,exchangetransfusionsarepreferredtoavoidthetheoreticalriskofincreasingbloodviscosity.

Recommendations

1.25.4.Forchildrenwithsicklecelldiseasewhoare?2yearsofage,werecommendscreeningforstrokeusingtranscranialDopplerimaging.IftranscranialDopplerimagingisunavailable,werecommendintermittentscreeningwithMRI(Grade1C).

1.25.5.Forchildrenwithsicklecelldiseasewhohaveischemicstroke,werecommendtherapywithIVhydrationand?30%exchangetotalhemoglobintransfusionto(Gradereduce1hemoglobinC).

Slevelsto1.25.6.Forchildrenwithsicklecelldiseasewhohaveischemicstroke,afteraninitialexchangetransfusionwesuggestalong-termtransfusionprogram(Grade2C).1.26Purpurafulminans

Althoughrare,themostcommonlyreportedhomozy-goteprothromboticdisorderpresentingduringthenew-CHEST/126/3/SEPTEMBER,2004SUPPLEMENT

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bornperiodisPCdeficiency.HomozygotePSdeficiencyisevenlesscommon.441–468AllpatientspresentinginthenewbornperiodhadundetectablelevelsofPC(orPS),whereaschildrenwithdelayedpresentationhaddetect-ablelevelsrangingbetween0.05and0.20U/mL.

TheclassicalclinicalpresentationofhomozygousPC/PSdeficiencyconsistsofcerebralorophthalmicdamage(orboth)thatoccurredinutero,theoccurrenceofpurpurafulminanswithinhoursordaysofbirth,and,onrareoccasions,large-vesselthrombosis.Purpurafulminansisanacute,lethaldisseminatedintravascularcoagulationsyndromethatischaracterizedbyrapidlyprogressivehemorrhagicnecrosisoftheskinduetodermalvascularthrombosis.469–471Theskinlesionsstartassmall,ecchy-moticsitesthatincreaseinaradialfashion,becomepurplishblackwithbullae,andthenturnnecroticandgangrenous.469,471Thelesionsoccurmainlyontheextrem-itiesbutcanoccuronthebuttocks,abdomen,scrotum,andscalp.Theyalsooccuratpressurepoints,atsitesofpreviouspunctures,andatpreviouslyaffectedsites.Af-fectedinfantsalsohavesecondaryhemorrhagiccomplica-tions.

ThediagnosisofinfantswithhomozygousPC/PSdefi-ciencyisbasedontheappropriateclinicalpicture,aPC/PSlevelthatisusuallyundetectable,aheterozygousstateintheparents,and,ideally,identificationofthemoleculardefect.ThepresenceofverylowlevelsofPC/PSintheabsenceofclinicalmanifestationsandofafamilyhistorycannotbeconsidereddiagnosticbecausephysiologicplasmalevelscanbeaslowas0.12U/mL.

Initialtreatment

ThediagnosisofhomozygousPC/PSdeficiencyisusu-allyunanticipatedandismadeatthetimeoftheclinicalpresentation.Althoughnumerousformsofinitialtherapyhavebeenused,theadministrationofFFP,10to20mL/kgevery6to12h,isusuallytheformoftherapythatismostreadilyavailable.472PlasmalevelsofPCachievedwiththesedosesofFFPvaryfrom15to32%at30minaftertheinfusion,andfrom4to10%at12h.451PlasmalevelsofPS(whichisentirelyboundtoC4b)were23%at2hand14%at24h,withanapproximatehalf-lifeof36h.462DosesofPCconcentratehaverangedfrom20to60U/kg.Inonestudy,462adoseof60U/kgresultedinpeakPClevelsof?0.60U/mL.Replacementtherapyshouldbecontinueduntilalloftheclinicallesionsresolve,whichisusuallyat6to8weeks.Inadditiontotheclinicalcourse,plasmad-dimerconcentrationsmaybeusefulformonitoringtheeffectivenessofPCreplacement.124

Long-termtherapy

Themodalitiesusedforthelong-termmanagementofinfantswithhomozygousPC/PSdeficiencyincludedoralanticoagulationtherapy,replacementtherapywitheitherFFPorPCconcentrate,andlivertransplantation.459Whenoralanticoagulationtherapyisinitiated,replacementther-apyshouldbecontinueduntiltheINRisinthetherapeu-ticrangesothatskinnecrosiscanbeavoided.ThetherapeuticrangefortheINRcanbeindividualizedto

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someextentbutisusuallybetween2.5and4.5.TherisksoforalanticoagulationtherapyincludebleedingwithhighINRsandrecurrentpurpuriclesionswithlowINRs.ThefrequentmonitoringofINRvaluesisrequiredifthesecomplicationsaretobeavoided.

Recommendations

1.26.1.ForneonateswithhomozygousPCdeficiency,werecommendtheadministrationofeither10to20mL/kgFFPevery12horPCconcentrate,whenavailable,ataconcentrationof20to60U/kguntiltheclinicallesionsresolve(Grade1C?).

1.26.2.Wesuggestlong-termtreatmentwithVKAs(Grade2C),LMWH(Grade2C),PCreplacement(Grade1C?),orlivertransplantation(Grade2C).

SummaryofRecommendations

1.1VTE

NeonateswithVTE

1.1.1.WesuggesttreatmentwitheitherUFHorLMWH,orradiographicmonitoringandanticoagulationtherapyifextensionoccurs(Grade2C).

1.1.2.Wesuggestthatifclinicianselecttreatmentwithanticoagulationtherapy,theyadministerUFHorLMWH,andsubsequentlyadministerLMWHfor10daysto3months(Grade2C).

1.1.3.WesuggestthatcliniciansadjustthedoseofUFHtoprolongtheaPTTcorrespondingtoananti-FXalevelof0.35to0.7U/mL(Grade2C).

1.1.4.WesuggestthatcliniciansadjustthedoseofLMWHtoachieveananti-FXalevelof0.5to1.0U/mL(Grade2C).

1.1.5.Wesuggestthatifthethrombusextendsfollowingthediscontinuationofheparintherapy,cliniciansadmin-isterVKAsorextendedLMWHtherapy(Grade2C).1.1.6.WesuggestthatcliniciansnotusethrombolytictherapyforthetreatmentofVTEsinneonatesunlessthereismajorvesselocclusionthatiscausingthecriticalcompromiseoforgansorlimbs(Grade2C).Ifthrombo-lytictherapyisused,wesuggestsupplementationwithplasminogen(ie,FFP)immediatelypriortothrombolysis(Grade2C).

1.1.7.Wesuggestthat,ingeneral,cliniciansshouldremoveeitherCVLsorUVCsthatareinsitu.However,ifeitherCVLsorUVCsarestillinplaceatthecompletionoftheabovetherapy,wesuggestprophylacticdosingwithLMWHtopreventrecurrentVTEsuntilsuchtimeastheCVLorUVCisremoved(bothGrade2C).

1.2.Systemicvenousthromboembolicdiseaseinchildren

FirstTEforchildren(?2monthsofage)

1.2.2.WerecommendtreatmentwithIVheparinsuffi-cienttoprolongtheaPTTtoarangethatcorrespondsto

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ananti-FXalevelof0.35to0.7U/mLorwithLMWHsufficienttoachieveananti-FXalevelof0.5to1.0U/mL4hafteraninjection(Grade1C?).

1.2.2.WerecommendinitialtreatmentwithheparinorLMWHfor5to10days(Grade1C?).ForpatientsinwhomsubsequentVKAswillbeused,werecommendbeginningoraltherapyasearlyasday1anddiscontinuingheparin/LMWHtherapyonday6iftheINRisinthetherapeuticrangeontwoconsecutivedays(Grade1C?).FormassivePEsorextensiveDVT,werecommendalongerperiodofheparinorLMWHtherapy(Grade1C?).

1.2.3.WesuggestcontinuinganticoagulanttherapyforidiopathicTEsforatleast6monthsusingVKAstoachieveatargetINRof2.5(INRrange,2.0to3.0)or,alternatively,LMWHtomaintainananti-FXalevelof0.5to1.0U/mL(Grade2C).

Underlyingvaluesandpreferences:Thesuggestiontoadministeranticoagulationtherapytochildrenwithidio-pathicDVTforatleast6monthsratherthanonalifelongbasisplacesarelativelyhighvalueontheavoidanceoftheknownriskofbleedingsecondarytoanticoagulanttherapyinyoungactiveadults,andlessimportanceontheun-knownriskofrecurrenceintheabsenceofanongoingclinicalprecipitatingfactor.

1.2.4.WesuggestthatforsecondaryTEsanticoagulanttherapybecontinuedforatleast3monthsusingVKAstoachieveatargetINRof2.5(INRrange,2.0to3.0)or,alternatively,usingLMWHtomaintainananti-FXalevelof0.5to1.0U/mL(Grade2C).

1.2.5.Wesuggestthat,inthepresenceofongoingriskfactorssuchasactivenephroticsyndrome,ongoingaspar-aginasetherapy,oradministrationofalupusanticoagu-lant,anticoagulanttherapyineithertherapeuticorpro-phylacticdosescontinueuntiltheriskfactorhasresolved(Grade2C).

1.2.6.WesuggestthatcliniciansnotusethrombolytictherapyroutinelyforthetreatmentofvenousTEinchildren(Grade2C).Treatmentneedstobeindividual-ized,andbasedonthesizeandlocationofthethrombus,andthedegreeoforgancompromise.Ifthrombolytictherapyisused,inthepresenceofphysiologicorpatho-logicdeficienciesofplasminogen,wesuggestsupplemen-tationwithplasminogen(ie,FFP)[Grade2C].

RecurrentidiopathicTEsinchildren

1.2.7.WerecommendindefinitetherapywitheithertherapeuticorprophylacticdosesofVKAs(Grade1C?).WesuggestLMWHtherapyasanalternativeifVKAtherapyistoodifficult(Grade2C).

RecurrentsecondaryTEsinchildren

1.2.8.Wesuggestthat,followingtheinitial3monthsoftherapy,anticoagulationtherapybecontinuedforatleastafurther3monthsoruntilremovalofanyprecipitatingfactors(Grade2C).

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CVL-relatedthrombosis

TherearetwoaspectstothemanagementofCVL-relatedthrombosis.First,managementoftheCVLitselfand,second,anticoagulationtherapy.

1.2.9.WesuggestthatiftheCVLisnolongerrequired,orisnonfunctioning,itberemoved(Grade2C).Wesuggestatleast3to5daysofanticoagulationtherapypriortoitsremoval.IfCVLaccessisrequiredandtheCVLinvolvedisstillfunctioning,wesuggestthattheCVLremaininsitu(Grade2C).Anticoagulationtherapyshouldbeadministeredasdescribedinrecommendations1.2.1to1.2.6.

1.2.10.ForchildrenwithafirstCVL-relatedDVTaftertheinitial3monthsoftherapy,wesuggestthatprophy-lacticdosesofVKAs(INRrange,1.5to1.8)orLMWH(anti-FXalevelrange,0.1to0.3)beadministereduntiltheCVLisremoved(Grade2C).

1.2.11.ForchildrenwithrecurrentCVL-relatedTEsaftertheinitial3monthsoftherapy,wesuggestprophy-lacticdosesofVKAs(INRrange,1.5to1.8)orLMWH(anti-FXalevelrange,0.1to0.3)becontinueduntiltheremovaloftheCVL.Iftherecurrenceoccurswhilechildrenarereceivingprophylactictherapy,wesuggestcontinuingtherapeuticdosesuntiltheCVLisremovedorforaminimumof3months(Grade2C).1.3RVT

1.3.1.ForunilateralRVTintheabsenceofuremia,andintheabsenceofextensionintotheIVC,wesuggestsupportivecarewithcarefulmonitoringoftheRVTforextension(Grade2C).Alternatively,wesuggestanticoag-ulationtherapywithUFHorLMWH(Grade2C).1.3.2.ForunilateralRVTthatdoesextendintotheIVC,wesuggestanticoagulationtherapywithUFHorLMWHfor6weeksto3months(Grade2C).

Remark:Thetherapeuticrangeisthesameasthatforthetreatmentofvenousthrombosis.

1.3.3.ForbilateralRVTwithvariousdegreesofrenalfailure,wesuggesttherapywithUFH(andnotLMWH)andthrombolytictherapy(Grade2C).1.4CVLprophylaxis

1.4.1.ForchildrenWithCVLs,werecommendagainstroutineprimaryprophylaxis(Grade1B).

1.4.2.Forchildrenreceivinglong-termhomeTPN,wesuggestantithromboticprophylaxis.Wesuggestcontinu-oustherapywithVKAs(targetINR,2to2.5)or,alterna-tively,forthefirst3monthsaftereachCVLisinserted(allGrade2C).

Remark:Theoptimaldruganddoseareunknown.1.5PrimaryprophylaxisforBTshuntsinneonates1.5.1.ForneonateshavingBTshunts,wesuggesttherapywithintraoperativeheparinfollowedbyeither

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aspirin(5mg/kg/d)ornofurtheranticoagulanttherapy(Grade2C).

1.6Primaryprophylaxisforstage1Norwoodpro-ceduresinneonates

1.6.1.ForpatientswhohaveundergonetheNorwoodprocedure,wesuggestheparintherapyimmediatelyaftertheprocedure(Grade2C).

1.8PrimaryprophylaxisforFontansurgeryinchildren

1.8.1.ForchildrenafterFontansurgery,wesuggesttherapywithaspirin(5mg/kg/d)ortherapeuticheparinfollowedbyVKAstoachieveatargetINRof2.5(INRrange,2to3)[Grade2C].

Remark:Theoptimaldurationoftherapyisunknown.Whetherpatientswithfenestrationsrequiremoreinten-sivetherapyuntilfenestrationclosureisunknown.1.9Primaryprophylaxisforendovascularstentsinchildren

1.9.1.Forchildrenhavingendovascularstentsinserted,wesuggesttheadministrationofheparinperioperatively(Grade2C).

1.10Primaryprophylaxisfordilatedcardiomyop-athyinneonatesandchildren

1.10.1.Forchildrenwithcardiomyopathy,wesuggestthattheyreceivetherapywithVKAstoachieveatargetINRof2.5(INRrange,2to3)commencingnolaterthanatthetimeoftheiractivationonacardiactransplantwaitinglist(Grade2C).

Underlyingvaluesandpreferences:OursuggestionfortheadministrationofVKAsplacesahighvalueonavoidingthromboticcomplications,andarelativelylowvalueonavoidingtheinconvenience,discomfort,andlimitationsofanticoagulantmonitoringinchildrenwhohaveapoten-tiallycurativetherapy(fortheircardiomyopathy)availabletothem.

1.11Primaryprophylaxisforbiologicalprostheticheartvalvesinchildren

1.11.1.Forchildrenwithbiologicalprostheticheartvalves,werecommendtreatmentaccordingtotheadultguidelines(seearticlebySalemetalinthissupplement)(Grade1C?).

1.12Primaryprophylaxisformechanicalpros-theticheartvalvesinchildren

1.12.1.Forchildrenwithmechanicalprostheticheartvalves,werecommendtheadministrationofVKAsfollow-ingadultguidelines(seearticlebySalemetalinthissupplement)fortheintensityoftherapy(ie,targetINRs)[Grade1C?].

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1.12.2.InchildreninwhomadditionalantithrombotictherapyisrequiredduetolackofresponsetotherapywithVKAsoracontraindicationtotherapywithfull-doseVKAs,wesuggestaddingtherapywithaspirin(6to20mg/kg/d)[Grade2C].

1.14Thromboprophylaxisforcardiaccatheteriza-tioninneonatesandchildren

1.14.1.ForneonatesandchildrenrequiringCCviaanartery,werecommendIVheparinprophylaxis(Grade1A).

1.14.2.Wesuggesttheuseofheparindosesof100to150U/kgasabolus.Furtherdosesmayberequiredinprolongedprocedures(bothGrade2B).

1.14.3.ForprophylaxisforCC,werecommendagainstaspirintherapy(Grade1B).

1.15Femoralarterythrombosisfollowingcardiaccatheterization

1.15.1.Forchildrenorneonateswithafemoralarterythrombosis,werecommendtherapeuticdosesofIVhep-arin(Grade1C).Wesuggesttreatmentforatleast5to7days(Grade2C).

Remark:Theoptimaldurationoftherapyisunknown.1.15.2.Forchildrenorneonateswithlimb-threateningororgan-threatening(viaproximalextension)femoralarterythrombosiswhofailtorespondtoinitialheparintherapy,andwhohavenoknowncontraindications,werecommendtheadministrationofthrombolytictherapy(Grade1C).

1.15.3.Forchildrenwithfemoralarterythrombosisinselectedcases,wesuggestsurgicalintervention,inparticularwhenthereisacontraindicationtothrombolytictherapy,orwhenorganorlimbdeathisimminent(Grade2C).1.16Peripheralarterythrombosis

1.16.1.Forneonatesandchildrenwithperipheralarte-rialcathetersinsitu,werecommendtheadministrationoflow-doseheparinthroughthecatheter,preferablybycontinuousinfusion,toprolongthecatheterpatency(Grade1A).

1.16.2.Forchildrenwithaperipheralarterialcatheter-relatedTE,wesuggesttheimmediateremovalofthecatheter(Grade2C).Wesuggestsubsequentanticoagu-lationtherapywithorwithoutthrombolysis,dependingontheclinicalsituation(Grade2C).

1.18AorticthrombosissecondarytoUACsinneo-nates

1.18.1.ForneonateswithUACs,wesuggesttherapywithlow-doseheparininfusion(1to5U/h)[Grade2A].1.18.2.WesuggestthataorticthrombosissecondarytoUACsbemanagedbythesameprinciplesasthoseforfemoralarterythrombosissecondarytocardiaccatheters.

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Ifthereisevidenceofrenalfailure,thenurgentrestora-tionofrenalbloodflowisrequired,andwesuggestthrombolysisorthrombectomy(allGrade2C).1.19Spontaneousaorticthrombosisinneonates1.19.1.Forchildrenexperiencingspontaneousaorticthrombosiswithevidenceofrenalischemia,wesuggesturgent,aggressiveuseofthrombolyticorsurgicaltherapy,supportedbyanticoagulationtherapywithheparinorLMWH(Grade2C).

1.20Kawasakidiseaseinchildren

1.20.1.Werecommendaspirintherapyinhighdoses(ie,80to100mg/kg/dduringtheacutephase,forupto14days)asananti-inflammatoryagent,theninlowerdoses(ie,3to5mg/kg/dfor?7weeks)asanantiplateletagent(Grade1C?).

1.20.2.WerecommendtherapywithIVgammaglobu-lin(2g/kgasasingledose)within10daysoftheonsetofsymptoms(Grade1A).

1.21AnticoagulationtherapyforKawasakidiseaseinchildrenwithgiantaneurysms

1.21.1.Inchildrenwithgiantcoronaryaneurysmsfol-lowingKawasakidisease,wesuggesttherapywithwarfarin(targetINR,2.5;INRrange,2.0to3.0)inadditiontolow-doseaspirin(Grade2C).

1.22Sinovenousthrombosisinneonates

1.22.1.ForneonateswithCSVT,withoutlargeischemicinfarctionsorICH,wesuggestinitialtreatmentwitheitherUFHorLMWHfollowedbytreatmentwithLMWHfor3months(Grade2C).

1.22.2.ForneonateswithCSVT,withlargeischemicinfarctionsorICH,wesuggestradiographicmonitoringandthecommencementofanticoagulationtherapyifextensionoccurs(Grade2C).

1.23Sinovenousthrombosisinchildren

1.23.1.ForchildrenwithCSVT,wesuggesttreatmentfor5to7dayswitheitherUFHorLMWHfollowedbytreatmentwithLMWHorVKAs(targetINR,2.5;INRrange,2.0to3.0)for3to6monthseveninthepresenceofalocalizedhemorrhagicinfarction(Grade2C).1.24AISinneonates

1.24.1.ForneonateswithnoncardioembolicAIS,wesuggestthatcliniciansdonotuseanticoagulationoraspirintherapy(Grade2C).

1.24.2.ForneonateswithcardioembolicAIS,wesug-gestanticoagulationtherapywitheitherUFHorLMWHfor3months(Grade2C).

1.25Arterialischemicstrokeinchildren

1.25.1.ForchildrenwithAIS,wesuggesttreatmentwithUFHorLMWHfor5to7daysanduntilcardioembolicstrokeorvasculardissectionhasbeenexcluded(Grade2C).

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1.25.2.ForchildrenwithAISandcardioembolicstrokeorvasculardissection,wesuggesttreatmentfor5to7dayswithUFHorLMWHfollowedbytreatmentwithLMWHorVKAsfor3to6months(Grade2C).

1.25.3.ForallchildrenwithAIS,wesuggesttreatmentwith2to5mg/kg/daspirinafteranticoagulationtherapyhasbeendiscontinued(Grade2C).

1.25.4.Forchildrenwithsicklecelldiseasewhoare?2yearsofage,werecommendscreeningforstrokeusingtranscranialDopplerimaging.IftranscranialDopplerimagingisunavailable,werecommendintermittentscreeningwithMRI(Grade1C).

1.25.5.Forchildrenwithsicklecelldiseasewhohaveischemicstroke,werecommendtherapywithIVhydrationand?30%exchangeoftotaltransfusionhemoglobintoreduce(Gradehemoglobin1C).

Slevelsto1.25.6.Forchildrenwithsicklecelldiseasewhohaveischemicstroke,afteraninitialexchangetransfusionwesuggestalong-termtransfusionprogram(Grade2C).1.26Purpurafulminans

1.26.1.ForneonateswithhomozygousPCdeficiency,werecommendtheadministrationofeither10to20mL/kgFFPevery12horPCconcentrate,whenavailable,ataconcentrationof20to60U/kguntiltheclinicallesionsresolve(Grade1C?).

1.26.2.Wesuggestlong-termtreatmentwithVKAs(Grade2C),LMWH(Grade2C),PCreplacement(Grade1C?),orlivertransplantation(Grade2C).

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