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PediatricThromboembolism

PediatricThromboembolism
Author:ScottCHoward,MDChiefEditor:RobertJArceci,MD,PhDmore...
Updated:Aug15,2014

Background
Althoughtheincidenceofvenousthromboembolism,aleadingcauseofadultmorbidityandmortality,islowerin
childrenthaninitisinadults,themorbidityassociatedwithitisclinicallysignificant.Thromboembolism,orthe
developmentofaclotwithinbloodvessels,canoccurinarteriesorveins,butarterialthromboembolism,whichis
alsoanimportantcauseofmorbidityinadults,islesscommoninchildrenandisonlybrieflyaddressedinthis
article.(SeeEpidemiologyandPrognosis.)
In1845,Virchowpostulatedthat3factorswereimportantinthedevelopmentofthrombosis:(1)impairmentof
bloodflow(stasis),(2)vascularinjury,and(3)alterationsoftheblood(hypercoagulability).Thesefactorsalsoplaya
roleinpediatricthrombosis(seethediagrambelow).(SeeEtiology.)

Virchowtriadforthepathophysiologyofthrombusformation.

Ahighindexofsuspicionforthromboembolismisrequiredfortimelydiagnosisindeed,manyearlyreportsonthis
conditionwerebasedonautopsydata.Symptomscanbenonspecificandincludetachypnea,tachycardia,fever,
pleuriticchestpain,cough,shortnessofbreath,and(lesscommonly)hemoptysis.Deepvenousthrombosis(DVT)is
absentinchildrenwithpulmonaryembolism(PE)moreoftenthanitisinadults.(SeePresentationandWorkup.)
Riskfactorsforthromboembolismincludethepresenceofacentralvenouscatheter,immobility,heartdisease,a
ventriculoatrialshunt,trauma(especiallyfractures),cancer,surgery,infection,dehydration,shock,estrogen
containingcontraceptives,pregnancy,smoking,andobesity.(SeeEtiology.)[1]
Thediagnosisandtreatmentofthrombosisinchildrenwereinitiallybasedonstandardsofcareforadults.However,
sincetheearly1990s,pediatricdatahaveemergedthatstressdifferencesinthromboembolismetiology,
pathophysiology,andanticoagulantdrugpharmacokineticsinchildren.(SeeEtiology,Presentation,Workup,
Treatment,andMedication.)

Physiology
Thephysiologyofhemostasisisremarkablycomplexandreflectsafinebalancebetweenanuninterruptedflowof
blood(ie,fluid)andarapid,localizedresponsetovascularinjury(ie,clotting).
Theprocessofhemostasisistraditionallydividedintoacellularphaseandafluidphase.Theformerinvolves
plateletsandthevascularwall,andthelatterinvolvesplasmaproteins.
Thefluidphaseisdividedintothefollowing3processes,abnormalitiesinanyofwhichcancontributeto
hypercoagulableorhypocoagulablestates(seethediagrambelow):
Themultiplestepzymogenpathwaythatleadstothrombingeneration
Thrombininducedformationofafibrinclot
Complexfibrinolyticmechanismsaimedatlimitingclotpropagation

Coagulationcascade.Solidarrowsrepresentactivationevents,dashedarrowsrepresentinhibitionevents,anddottedlines
withcirclesrepresentinactivationevents.a=activeAPC=activatedproteinCF=factorFDP=fibrindegradation
productsHMW=highmolecularweightPAI1=plasminogenactivatorinhibitor1PL=phospholipidTM=
thrombomodulintPA=tissuetypeplasminogenactivatoruPA=urokinaseplasminogenactivatorXL=crosslinked.

Regardingthefluidphase,manyagedependentdifferencesarepresentinthehemostaticsystemofinfantsand
children.AdultlevelsofthevitaminKdependentcoagulationfactorsII,IX,andX,aswellascontactfactors,are
notachieveduntilage36months.levelsofthrombininhibitors,suchasantithrombinandheparincofactorII,are
similarlylowatbirththatis,theyareintherangesthatincreasetheriskforheterozygousadultstodevelop

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thromboembolism.
levelsofalpha2macroglobulinarehigherininfantsandchildrenthaninadults.Conversely,levelsofproteinCand
Sarelowatbirth.ProteinSlevelsapproachadultvaluesbyage36months,butproteinClevelsremainloweven
intochildhood.Plasminogenlevelsarelowinnewbornsandinfants,whichhasimplicationsfortreatmentof
thromboembolisminnewborns.Thrombingenerationisdecreased(probablybecauseoflowprothrombinlevels)and
delayedinnewborns,whohaveahigherriskforbleedingrelativetoadults.

Patienteducation
Clearlydefineactivityrestrictions,especiallyinthecaseofadolescents.Ifachildisreceivingoralanticoagulation,
reviewthevitaminKcontentofvariousfoodswiththefamily.Theproperfittingandneedfordailyuseof
compressionstockingstopreventpostthromboticsyndromeafterlowerextremityvenousthrombosismustbe
emphasized.Aftervenousthrombosisoccurs,therecurrenceriskcanbeminimizedbyavoidingadditionalrisk
factors,sopatientsshouldreceiveeducationfocusedonreducingobesity,avoidingsmoking,andavoidingoral
contraceptives(andpregnancy).

Etiology
Advancesintechnologyhaveimprovedthesurvivalofinfantswhoarebornprematurelyandofchildreninintensive
careunits(ICUs).Approximately95%ofchildrenwithDVTand/orPEhaveoneormoreunderlyingriskfactors
mosthavemorethanone.Therefore,athoroughevaluationiswarranted,evenwhenthecauseof
thromboembolismseemsobvious.

Useofarterialcatheters
Theuseofarterialcathetersisthemostcommonriskfactorforarterialthromboembolisminchildren.Cardiac
catheterizationthroughthefemoralarterytomanagecongenitalheartdiseaseisafrequentcause.
Prophylaxiswithheparin(100150U/kg)duringtheprocedurelowerstheincidenceofthrombosisfrom40%to8%in
childrenyoungerthan10years.Inneonates,catheterizationoftheumbilicalarteryposesriskssimilartothese.The
absoluteincidenceofthrombosisis1090%whenangiographicdiagnosticmethodsareused.

Useofcentralvenouscatheters
Centralvenouscatheterassociatedthrombosiswasreportedin29%ofchildreninareportbyNussetalandin33%
ofchildreninaCanadianseries. [2]Thrombosisisassociatedwithacentralvenouscatheterin80%ofnewbornsand
50%ofchildrenwithupperextremitythrombosis. [3]
AccordingtoastudybySandovaletal,theincidenceofclinicallyevidentDVTinhospitalizedchildrenincreased
from0.3casesto28.8casesper10,000hospitaladmissionsbetween1992and2005,withcentralvenouscatheters
accountingfor45%ofDVTsthatdevelopedduringthepatientshospitalstay(vsthosethatwerealreadypresenton
admission). [4]

Antiphospholipidantibodysyndrome
Antiphospholipidantibodies,whicharedetectedbyfindingpositivelupusanticoagulantoranticardiolipinantibodies,
areassociatedwiththrombosisinadultsandchildren.In2studiesofchildrenwithsystemiclupuserythematosus
andassociatedanticardiolipinantibodies,theincidencesofthromboembolismwere9.2%and17%.However,most
childrenwithantiphospholipidantibodysyndromeacquireitincidentallyanddonothavesystemiclupus
erythematosus.
Inonestudy,inwhich95childrenwithlupusanticoagulantwerefollowedforamedianof5.3years,bleeding
symptomswerefoundinapproximately10%ofthesechildren,while5%hadathromboticevent.

Disseminatedintravascularcoagulation
Sepsisanddisseminatedintravascularcoagulationhavebeenassociatedwiththromboembolisminchildrenandin
adults.Microvascularthrombosisconsumesclottingfactors,predisposingthepatienttohemorrhageand
thromboembolism.Treatmentoftheunderlyingcauseisessential.

Surgery,immobilization,andprolongedbedrest
Theeffectsofsurgery,immobilization,andprolongedbedrestonthromboembolismriskhavebeenstudied
extensivelyinadults,andevidencebasedrecommendationsforprophylaxisagainstthromboembolismhavebeen
widelydisseminated.
Comparedwithadults,childrenhaveamuchlowerriskofthrombosisaftersurgery.Therefore,prophylactic
administrationofheparinorlowmolecularweightheparin(LMWH)isnotrecommendedforchildrenunless
additionalriskfactorsarepresent(eg,obesity,oralcontraceptiveuse,cancer,centralvenouscatheter). [5]

Malignancy
Malignancyassociatedthromboembolismhasbeenstudiedmostextensivelyinchildrenwithacutelymphoblastic
leukemia.Theunderlyingmechanismsarecomplexandincludetheeffectofleukemiaitselfandtheuseof
chemotherapy,especiallyLasparaginase.Inaddition,permanentcentralvenouscathetersareplacedinmany
childrenwithmalignancies.

Useofestrogencontainingmedications
Oralcontraceptives,especiallythosethatcontainestrogen,areassociatedwitha4foldincreaseintheriskof
venousthrombosisanda22foldincreaseintheriskofcerebralthrombosis.Thisriskmaybeexplainedbythe
acquisitionofresistancetoactivatedproteinC.Administrationoforalcontraceptivestopatientswhoare
heterozygousforthefactorVLeidenmutationincreasestheriskofvenousthromboembolism35foldto50fold.In
womenwithantithrombin,proteinC,orproteinSdeficiencywhoaretakingoralcontraceptives,theriskrises6fold.

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However,theabsoluteriskisonly0.3%peryear,andpregnancyitselfproducesaprothromboticstatethus,benefits
mustbeweighedagainstriskswhenhelpingpatientstodecidewhetherornottousecontraceptivesandwhich
methodtochoose.

Nephroticsyndrome
Childrenwithproteinuriaatlevelsofmorethan0.5g/daymayhavealossofanticoagulantproteins(eg,
antithrombin),whichincreasestheriskofthromboembolism.Mostthromboembolismsdevelopwithinseveral
monthsofdiagnosis.Arterialthromboembolismandvenousthromboembolismcanoccurrenalveinthrombosisis
mostcommon.

Heparininducedthrombocytopenia
Heparininducedthrombocytopeniaischaracterizedbyadecreaseofmorethan50%intheplateletcountaftera
patientisgivenunfractionatedheparinfor5daysorlonger,andinasmallernumberofpatientstreatedwithLMWH.
Heparininducedthrombocytopeniacanbecomplicatedbyvenousandarterialthrombosis,butahighindexof
suspicionisneededtorecognizethissyndromeinchildren,includingthosewhoarereceivingonlyheparinflushesto
maintainthepatencyofintravenousorcentrallines.Managementincludescessationofallformsofheparinand
administrationofadirectthrombininhibitoruntiltheplateletcountnormalizesandthepatientcanbetransitionedto
warfarinanticoagulation.

Inheritedprothromboticdisorders
Severaldominantlyinheriteddeficienciesorabnormalitiesofproteinsinvolvedinthecoagulationandfibrinolytic
pathwaysarenowrecognized.Occasionally,morethan1suchabnormalitymaycoexistinasinglepatient.Therisk
ofvenousthromboembolisminpatientswiththeseabnormalitiesdependsnotonlyonthenumberofconcomitant
inheritedriskfactorsbutalsoonthenumberofacquiredriskfactorssuchasorthopedicsurgeryortrauma,
immobility,pregnancy,useoforalcontraceptives,anddehydration.

FactorVLeiden
ResistancetoactivatedproteinCduetoapointmutationinfactorV(namedfactorVLeiden,afterthecityinwhich
thediscoverywasmade)isthemostcommongeneticriskfactorassociatedwithvenousthrombosisinadultsand
children.ThismutationpreventscleavageofactivatedfactorVbyactivatedproteinCandthuspromotesongoing
clotdevelopment.
Approximately38%ofwhitesareheterozygousforthemutation,butmanyhavenohistoryofthrombosis.Several
pediatricstudieshavedemonstratedthat1050%ofchildrenwiththrombosisareheterozygousforthefactorV
Leidenmutation.
DoubleheterozygotesforfactorVLeidenandforproteinC,proteinS,orantithrombindeficiencyhavebeen
reportedtheseindividualshaveafurtherincreaseintheirriskofthrombosis.
AmongwomenwhoareheterozygousforfactorVLeidenwhoalsoaretakingoralcontraceptives,theriskof
thrombosisrises35fold.Evenso,veryfewdevelopthrombosisduringadolescence,andusuallyonlydosowhen
additionalriskfactorsarepresent.

Antithrombindeficiency
Producedintheliver,antithrombinisthemostimportantinhibitorofactivatedclottingfactors.Mostpatientswith
antithrombindeficiencyareheterozygous(withlevels<50%),andthrombosisinthispopulationisusuallyvenous.
Thrombosiscanoccurinchildrenasyoungas10years.
Homozygousdeficiencyofantithrombinisrarebutdevastating.Patientsusuallypresentwithinhoursofbirthand
haveextensivethrombosis.Mostinfantsdiesoonafterbirth.

ProteinCdeficiency
ProteinCdeficiencyisusuallytransmittedinanautosomaldominantmannerwithincompletepenetrance.
ThrombosisoccurringinassociationwithproteinCdeficiencyismostoftenvenousandinthelowerextremities.
DVTinheterozygotescanbeobservedasearlyastheteenageyears.Similartohomozygoteswithantithrombin
deficiency,homozygoteswithproteinCdeficiencyusuallypresentinthenewbornperiod,withpurpurafulminans.A
purifiedproteinCconcentrate(Ceprotin)hasbeendesignatedasanorphandrugforthetreatmentofproteinC
deficiency.
PatientswitheitherproteinCorproteinSdeficiencywhorequireanticoagulationcandevelopwarfarininducedskin
necrosisunlessheparinisstartedfirst.

ProteinSdeficiency
ProteinSdeficiencyissimilartoproteinCdeficiencyandantithrombindeficiency,exceptthatitenhancesan
individual'spredispositiontodeveloparterialthrombosis.MostproteinSisboundtoC4bindingprotein.Therefore,
onemustmeasurebothfreeandtotalconcentrationsofproteinStoruleoutadeficiency.
Asstatedabove,warfarininducedskinnecrosiscanoccurinpatientswitheitherproteinCorproteinSdeficiency
whorequireanticoagulation,unlessheparinisstartedfirst.

Hyperhomocysteinemia
Inadults,hyperhomocysteinemiaisanindependentriskfactorforarterialvasculardiseaseandvenousthrombosis.
Astudyof45childrenwithischemicstrokedemonstratedthattheiroddsratioformoderatehyperhomocysteinemia,
incomparisonwithcontrolsubjects,was4.4,indicatingthatitisariskfactorforpediatricvenousthrombosisaswell.
AGermanstudyof163childrenwithvenousthromboembolismshoweda3foldincreaseintheriskforthiscondition
amongsubjectswithelevatedfastinghomocysteinelevels. [6]Homozygousmutationsinthegeneforcystathionine

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betasynthetase,althoughrare,accountformostcasesofseverehyperhomocysteinemia.
Mildtomoderatehyperhomocysteinemiacanoccurinheterozygoteswithmutationsaffectingcystathioninebeta
synthetaseormethylenetetrahydrofolatereductase.

Prothrombingene20210Amutation
ATurkishstudyof32childrenwithcerebralinfarctsrevealedthat21.8%wereheterozygousfortheprothrombin
gene20210Amutation. [7]Studieshaveshownthatthismutationincreasestheriskforpediatricarterialthrombosis,
especiallyinthecentralnervoussystem(CNS).

Elevatedlipoprotein(a)levels
Elevatedlipoprotein(a)levelshavebeenfoundinchildrenwiththromboembolism.Otherdisorders,suchas
dysfibrinogenemiaandplasminogendeficiency,arerarebutshouldbeevaluatedforiftherestoftheworkupyields
negativeresults.

FactorsVIIIandXI
StudiesinadultshaveimplicatedelevatedlevelsoffactorVIIIandfactorXIasriskfactorsforthrombosis,but
whethertheyareriskfactorsinchildrenisunknown.

Congenitalheartdisease
Congenitalheartdiseasecanbeathromboembolicriskfactorforchildrenwithmechanicalorprostheticvalvesand
forthoseundergoingBlalockTaussigshuntplacementoraFontanprocedure.Asnotedabove,cardiac
catheterizationisthemostcommonriskfactorforarterialthrombosis.
Cardiogenicembolismduetoatrialfibrillationorcardiomyopathyisacauseofstrokeinchildrenandadults.
AstudybyYamamuraetalsuggestedthatinpatientswithconcurrentcongenitalheartdiseaseandasplenia,
thromboembolismismorelikelytodevelopduringmanagementofthediseasethanitisinpatientswhohave
congenitalheartdiseasebutarenotasplenic.Thestudyinvolved161patientswithcongenitalheartdiseasewho
underwentcardiaccatheterization46ofthepatientshadasplenia,and115patientsdidnot. [8]
Theinvestigatorsfoundthat,unlikethepatientswithoutasplenia,thosewhowereasplenichadpersistent
thrombocytosis.Therewasalsoahigherincidenceofthromboemboliccomplicationsintheasplenicpatientsthanin
thenonasplenicgroup(28%vs10%,respectively).Thefindingemphasizesthefactthatinchildren,usuallymultiple
riskfactorsmustbepresenttoleadtoasignificantincidenceofthrombosis.

Epidemiology
OccurrenceintheUnitedStates
Therateofvenousthromboembolisminpediatrictertiarycarehospitalsreportedlyunderwentasignificantincrease
between2001and2007.AstudybyRaffinietalfoundthattheannualrategrewfrom34to58casesper10,000
hospitaladmissions,ariseof70%.Accordingtothereport,theincreasedrateencompassednewborns,infants,
children,andadolescents. [9,10]

Internationaloccurrence
InaGermanstudy,byNowakGottletal,theincidenceofsymptomaticneonatalthromboembolismwas5.1cases
per100,000births. [11]

Race,sex,andagerelateddemographics
Althoughsomeprothromboticriskfactorsaremorecommoninparticularracialgroups,overallthereisnoevidence
tosuggestthatchildrenofanyparticularraceareathigherriskforthromboembolism.Withregardtosex
predilection,maleandfemalechildrenareequallyaffectedbythromboembolism.
Theincidenceofthromboembolismpeaksinnewbornsandinfantsyoungerthan1year,thenremainsverylowuntil
adolescence,whentheincidencebeginstoincrease. [9]

Prognosis
Potentialcomplicationsofthromboembolismincludethefollowing:
Recurrentthrombosis
Pulmonaryembolism
Postthromboticsyndrome
Bleeding
Death
Manychildrenwiththromboembolismhaveapersistentunderlyingriskfactor,suchascongenitalheartdisease.

Recurrentthromboembolism
Recurrencemayoccursecondarytoinadequateanticoagulationbecauseofaconcernaboutbleedingand/orthe
persistenceofunderlyingriskfactors,suchastheuseofacentralvenouscatheter.
AGermanstudyshowedthatanumberofunderlyinggeneticriskfactorsaffectedrecurrencerates.Childrenwithno
geneticriskfactorshada4.8%recurrencerate,whereasthosewith1geneticriskfactorhada17.6%recurrence
rate.Inchildrenwith2ormoregeneticriskfactors,theriskofrecurrencewasalmost50%.
Goldenbergetalnotedanincreasedrecurrencerateinchildrenwithvenousthromboembolismandelevatedlevels

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offactorVIIIand/orDdimerafter36monthsofanticoagulationtherapy. [12]

Postthromboticsyndrome
Postthromboticsyndromeconsistsofchronicallyswollen,painfulextremitieswithindurationoftheskin,ulceration,
andpigmentarychangessecondarytochronicvenousstasis.From2067%ofadultswithDVTdevelop
postthromboticsyndrome,whiletheCanadianregistryofpediatricDVTandPEdocumentedthesyndromein21
25%ofchildrenwithvenousthrombosis. [13,14]
Usingastandardizedscore,investigatorsinastudyfromtheHospitalforSickChildreninToronto,Canada,
observedpostthromboticsyndromein63%of153children.Casesweremildin83%andmoderatein17%. [15]The
mildcases,whichweredetectedonlybyuseofprospectiveobservationusingastandardmethodologyandtrained
personnel,wouldbeunlikelytoappearintheregistrycitedabove,whichexplainstheapparentlydiscrepantresults.
Treatmentofpostthromboticsyndromeconsistsoftheuseofelasticcompressionstockings,elevationofthe
extremityabovetheleveloftheheart,andadministrationofanalgesicsornarcoticsasnecessary.

ContributorInformationandDisclosures
Author
ScottCHoward,MDMember,DepartmentofOncology,DirectorofClinicalTrials,InternationalOutreach
Program,StJudeChildren'sResearchHospitalProfessor,UniversityofTennesseeHealthScienceCenter
CollegeofMedicine
ScottCHoward,MDisamemberofthefollowingmedicalsocieties:AmericanSocietyofHematology,American
SocietyofPediatricHematology/Oncology,andInternationalSocietyofPaediatricOncology
Disclosure:Nothingtodisclose.
ChiefEditor
RobertJArceci,MD,PhDDirector,Children'sCenterforCancerandBloodDisorders,Departmentof
Hematology/Oncology,CoDirectoroftheRonMatricariaInstituteofMolecularMedicine,PhoenixChildren's
HospitalEditorinChief,PediatricBloodandCancerProfessor,DepartmentofChildHealth,Universityof
ArizonaCollegeofMedicine
RobertJArceci,MD,PhDisamemberofthefollowingmedicalsocieties:AmericanAssociationforCancer
Research,AmericanAssociationfortheAdvancementofScience,AmericanPediatricSociety,AmericanSociety
ofHematology,andAmericanSocietyofPediatricHematology/Oncology
Disclosure:Nothingtodisclose.
AdditionalContributors
JamesLHarper,MDAssociateProfessor,DepartmentofPediatrics,DivisionofHematology/Oncologyand
BoneMarrowTransplantation,AssociateChairmanforEducation,DepartmentofPediatrics,Universityof
NebraskaMedicalCenterAssistantClinicalProfessor,DepartmentofPediatrics,CreightonUniversitySchoolof
MedicineDirector,ContinuingMedicalEducation,Children'sMemorialHospitalPediatricDirector,Nebraska
RegionalHemophiliaTreatmentCenter
JamesLHarper,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,American
AssociationforCancerResearch,AmericanFederationforClinicalResearch,AmericanSocietyofHematology,
AmericanSocietyofPediatricHematology/Oncology,CouncilonMedicalStudentEducationinPediatrics,and
HemophiliaandThrombosisResearchSociety
Disclosure:Nothingtodisclose.
JMartinJohnston,MDAssociateProfessorofPediatrics,MercerUniversitySchoolofMedicineDirectorof
Hematology/Oncology,TheChildren'sHospitalatMemorialUniversityMedicalCenterConsulting
Oncologist/Hematologist,StDamien'sPediatricHospital
JMartinJohnston,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatricsand
AmericanSocietyofPediatricHematology/Oncology
Disclosure:Nothingtodisclose.
PhilipMMonteleone,MDAssociateProfessor,DepartmentofPediatrics,DivisionofOncology,Universityof
PennsylvaniaandChildren'sHospitalofPhiladelphi
Disclosure:Nothingtodisclose.
MaryLWindle,PharmDAdjunctAssociateProfessor,UniversityofNebraskaMedicalCenterCollegeof
PharmacyEditorinChief,MedscapeDrugReference
Disclosure:Nothingtodisclose.

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