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Approachtotheadultwithunexplainedthrombocytopenia

Authors: JamesNGeorge,MD,DonaldMArnold,MD,MSc
SectionEditor: LawrenceLKLeung,MD
DeputyEditor: JenniferSTirnauer,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Feb2017.|Thistopiclastupdated:Jan09,2017.

INTRODUCTIONThrombocytopeniamaybeassociatedwithavarietyofconditions,withassociated
risksthatmayrangefromlifethreateningbleedingorthrombosis(eg,inheparininduced
thrombocytopenia[HIT])tonoriskatall.Atthetimeofinitialpresentation,thecausemaybeunclear
andthedirectionoftheplateletcounttrendmaynotbeknown.Theclinicianisfacedwithdistinguishing
amongmanypossiblecausesofthrombocytopeniaanddeterminingtherisksofbleeding,thrombosis,
andotherpotentialcomplications.

Herewediscussourapproachtotheadultpatientwithunexpectedthrombocytopenia,divided
accordingtoclinicalpresentation(eg,asymptomatic,associatedwithanothercondition,acutelyill
hospitalizedpatient).Thisapproachcanbeusedbytheprimarycarephysicianandtheconsulting
hematologist.Thrombocytopeniainneonatesandchildren,andthrombocytopeniaduringpregnancy
arediscussedseparately.(See"Causesofneonatalthrombocytopenia"and"Causesof
thrombocytopeniainchildren"and"Thrombocytopeniainpregnancy".)

DEFINITIONSANDAREASOFCONCERN

WhatisalowplateletcountThrombocytopeniaisdefinedasaplateletcountbelowthelowerlimit
ofnormal(ie,<150,000/microL[150x109/L]foradults).Degreesofthrombocytopeniacanbefurther
subdividedintomild(plateletcount100,000to150,000/microL),moderate(50,000to99,000/microL),
andsevere(<50,000/microL)[1].Severethrombocytopeniaconfersagreaterriskofbleeding,butthe
correlationbetweenplateletcountandbleedingriskvariesaccordingtotheunderlyingconditionand
maybeunpredictable.(See'Whentoworryaboutbleeding'below.)

Thenormaladultplateletcountrangeis150,000to450,000/microL,withmeanvaluesof266,000and
237,000/microLinfemalesandmales,respectively[2].Withinthatbroadnormalrange,adultwomen
haveslightlyhigherplateletcountsthanmen,youngerpeoplehavehigherplateletcountsthanolder
people,andnonHispanicBlackshavehigherplateletcountsthanWhites[3].Despitethewide
variationofplateletcountswithinthepopulation,thereislittlevariationoftheplateletcountinagiven
individualovertime.Asanexample,astudyofserialplateletcountsin3789individualsfoundthatthe
plateletcountrangeforanindividualwasrelativelynarrowdifferencesinplateletcountgreaterthan
98,000/microLoccurredinlessthan0.1percentofparticipants[2].Interestingly,therewasamodest
seasonalvariation,withplateletcountsapproximately5000/microLhigherinthefall/winterversusthe
spring/summer.Thiswidenormalrange,narrowindividualrange,andcontinuousdistributionhave
implicationsforevaluatinganyindividualpatient'splateletcount:

Asmallproportionofthepopulation(approximately2.5percent)willhaveabaselineplateletcount
lowerthan150,000/microL,becausenormalvaluesaretypicallydeterminedbasedonthe95%
confidenceintervalsaroundthemean.
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Anindividualcanhaveasignificantdecreaseinplateletcountandstillbewithinthe'normal'range
ofplateletcountsandthusnotbeflaggedasabnormal(eg,a50percentreductioninplatelet
countisconcerning,butthevaluemaystillbe150,000/microL).Suchareductionmaybe
clinicallysignificantandrequiresevaluation.Ataminimum,theplateletcountshouldberepeated.

Theseissueshighlighttheimportanceofobtainingpreviousplateletcounts(ifavailable)todetermine
whetherthecountisstableortrendingdownward.Arecentfallintheplateletcountby50percent,
evenifstillinthenormalrange,mayheraldsevereclinicalproblems,andrequiresactivefollowup.
(See'Overviewofourapproach'below.)

WhentoworryaboutbleedingBleedingisaconcerninpatientswithseverethrombocytopenia
however,thecorrelationbetweenplateletcountandbleedingriskisuncertain.Clinicalpredictorsof
bleedingincludepriorbleedingatasimilarplateletcountandthepresenceofwetpurpura(eg,in
mucosalmembranes).(See'Physicalexamination'below.)

Theconceptofa"safe"plateletcountisimprecise,lacksevidencebasedrecommendations,and
dependsonthedisorderandonthepatient(evenwiththesamedisorder)[4].Thefollowingmaybe
usedasguides,butshouldnotsubstituteforclinicaljudgmentbasedonindividualpatientanddisease
factors:

Surgicalbleedinggenerallymaybeaconcernwithplateletcounts<50,000/microL
(<100,000/microLforsomehighriskproceduressuchasneurosurgeryormajorcardiacor
orthopedicsurgery).

Severespontaneousbleedingismostlikelywithplateletcounts<20,000to30,000/microL,
especiallybelow10,000/microL.

Itisalsoimportanttoconsiderotherfactorsthatmayaffectbleedingrisk(eg,plateletfunctiondefects,
coagulationabnormalities).Whenpresent,thesefactorsmaycontributetobleedingriskandmaybe
moreconcerningthanthelowplateletcount.

TheroleofplateletfunctioninbleedingriskisillustratedbytherareinheriteddisorderBernardSoulier
syndrome(BSS),characterizedbythrombocytopeniaandimpairedplateletfunctioninwhichbleeding
isoutofproportiontothedegreeofthrombocytopenia.Similarly,patientswithsevereliverdiseaseor
disseminatedintravascularcoagulationmayhaveagreaterriskofbleedingfromcoagulationdefects
thanfromthethrombocytopenia.

Incontrast,individualswithhemostaticallynormalplatelets(eg,asseeninimmunethrombocytopenia
[ITP])generallydonothaveseverespontaneousbleedingevenwithverylowplateletcounts.(See
"Immunethrombocytopenia(ITP)inadults:Clinicalmanifestationsanddiagnosis",sectionon
'Correlationofbleedingandthrombocytopenia'.)

WhentoworryaboutthrombosisRarely,patientswiththrombocytopeniaareatriskfor
thrombosisratherthanbleeding.Whilemostoftheimplicateddisordersarerare,itisimportantto
considerthembecauseurgenttreatmentmaybeneededtopreventlifethreateningthromboticevents.

Examplesincludethefollowing:

HeparininducedthrombocytopeniaAsmallpercentageofpatientsexposedtoheparin(<5
percent)willdevelopheparininducedthrombocytopenia(HIT)inwhichantibodiestoaplatelet
factor4epitopeinducedbyheparincancausethrombocytopeniaandplateletactivation,leadingto
lifethreateningvenousand/orarterialthrombosis.Thisdiagnosisshouldbeconsideredina

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patientrecentlyexposedtoheparinwhodevelopsthrombocytopenia,thrombosis,anaphylaxis,or
skinreactions.Treatmentinvolvesimmediatediscontinuationofheparinandadministrationofa
nonheparinanticoagulant.Adiscussionofnonheparinanticoagulantsandevidencetosupport
theiruseispresentedseparately.(See"Clinicalpresentationanddiagnosisofheparininduced
thrombocytopenia"and"Managementofheparininducedthrombocytopenia".)

AntiphospholipidsyndromeTheantiphospholipidsyndrome(APS)candevelopinindividuals
withsystemiclupuserythematosus,othermedicalconditions(eg,infection,medications,cancer),
orinotherwisehealthyindividuals.Patientsmayhavevenousand/orarterialthrombosis.
Treatmentinvolvesanticoagulationoraspirin,andtreatmentofanyunderlyingcondition,as
discussedindetailseparately.(See"Clinicalmanifestationsofantiphospholipidsyndrome"and
"Treatmentofantiphospholipidsyndrome"and"Diagnosisofantiphospholipidsyndrome",section
on'OtherconditionsassociatedwithaPL'.)

DisseminatedintravascularcoagulationPatientswithdisseminatedintravascularcoagulation
(DIC)areatriskofbleedingorthrombosis,usuallyvenous.DICiscommonlyseeninacutelyill
patientswithsepsisormalignancy,butitcanalsobeseeninavarietyofotherconditions(table1).
Treatmentoftheunderlyingconditionisparamount.(See"Clinicalfeatures,diagnosis,and
treatmentofdisseminatedintravascularcoagulationinadults".)

ThromboticmicroangiopathyThromboticmicroangiopathies(TMAs)suchas
thrombocytopenicpurpura(TTP),hemolyticuremicsyndrome(HUS),ordruginducedTMA
(DITMA)areassociatedwithsmallvesselplateletrichthrombi.Thesemicrothrombicanoccurin
anyorganandcanbelifethreatening.Plasmaexchangemaybelifesavingandshouldbe
initiatedimmediatelyintheappropriateclinicalsetting.(See"Approachtothepatientwith
suspectedTTP,HUS,orotherthromboticmicroangiopathy(TMA)"and"AcquiredTTP:Initial
treatment"and"Druginducedthromboticmicroangiopathy".)

ParoxysmalnocturnalhemoglobinuriaParoxysmalnocturnalhemoglobinuria(PNH)isarare
conditioncausedbylossofglycosylphosphatidylinositolfromcellmembranes.Thrombosisof
intraabdominalveins(eg,hepatic,splenic,portal)andcerebralveinscanoccur,alongwith
hemolyticanemiaand/orothercytopenias.Treatmentdependsonthedegreeofanemia,the
presenceofthrombosis,andtheseverityoforganinvolvement.(See"Treatmentandprognosisof
paroxysmalnocturnalhemoglobinuria"and"Clinicalmanifestationsanddiagnosisofparoxysmal
nocturnalhemoglobinuria".)

PATHOPHYSIOLOGYThemajorpathophysiologicmechanismsofthrombocytopeniainclude
decreasedplateletproductioninthebonemarrowperipheralplateletdestructionbyantibodies
consumptioninthrombidilutionfromfluidresuscitationormassivetransfusionandsequestration
(pooling)ofplateletsinthespleeninindividualswithportalhypertensionand/orsplenomegaly.These
mechanismsareillustratedbythefollowingexamples:

BonemarrowdisordersPlateletsareproducedinthebonemarrowfrommegakaryocytes
(picture1),whicharederivedfrommultipotenthematopoieticprogenitorcells.Each
megakaryocyteproducesanestimated1000to5000platelets.Therateofplateletproductionis
35,000to50,000plateletspermicroLofblooddailyatsteadystateproductioncanbeincreased
uptoeightfoldduringtimesofincreaseddemand[5,6].(See"Megakaryocytebiologyandthe
productionofplatelets".)

Typically,bonemarrowdisordersthatimpairplateletproduction(eg,nutrientdeficiencies,
myelodysplasticsyndromes,infection/sepsis)alsoreduceproductionofotherbloodcells(ie,red

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bloodcells[RBC]andwhitebloodcells[WBC]),causingpancytopenia.Patientsmaypresentwith
symptomsofthrombocytopenia(eg,bleeding,petechiae)orsymptomsattributabletoanemia
and/orleukopenia(eg,fatigue/shortnessofbreath,infection).

Isolatedmegakaryocytelosscanalsooccasionallyoccur(eg,inresponsetoadrug).Inaddition,
primaryimmunethrombocytopenia(ITP)iscommonlyassociatedwithimpairedplatelet
production.(See"Immunethrombocytopenia(ITP)inadults:Clinicalmanifestationsand
diagnosis",sectionon'Pathogenesis'.)

Plateletdestruction/consumptionPlateletssurviveinthecirculationfor8to10days,after
whichtheyareremovedbymonocytesormacrophagesofthereticuloendothelialsystem(eg,liver
andspleen),perhapsasaresultofprogrammedapoptosis[7,8].Accelerateddestructionof
platelets(andpossiblymegakaryocytes)canoccurduetoantibodymediatedclearance.Anti
plateletantibodiescanbeinducedbysomemedicationsandingestedsubstances(eg,quinine)in
primaryITPorinsecondaryITP(ie,inthecontextofanotherautoimmunesyndromesuchas
systemiclupuserythematosus).(See"Druginducedimmunethrombocytopenia",sectionon
'MechanismsofDITP'.)

Combinedcytopeniasduetoantibodymediateddestructionofmorethanonebloodcelllinecan
alsooccurthetermEvanssyndromeisusedtorefertocombinedwarmautoimmunehemolytic
anemia(AIHA)andITP.Autoimmuneneutropeniacanalsooccurinthissetting.(See"Warm
autoimmunehemolyticanemia:Treatment",sectionon'Evanssyndrome'.)

Plateletconsumptionalsooccurswithinthrombiindisseminatedintravascularcoagulation(DIC)
andthromboticmicroangiopathiessuchasthrombocytopenicpurpura(TTP)orhemolyticuremic
syndrome(HUS).(See"PathophysiologyofacquiredTTPandotherprimarythrombotic
microangiopathies(TMAs)".)

DilutionAnadditionalmechanismofthrombocytopeniaisdilutionalthrombocytopenia,as
occursinthesettingofmassivefluidresuscitationormassivetransfusion.Plateletcountsare
reducedinproportiontothenumberofRBCunitstransfusedina24hourperiod[9,10].Ratiosof
plateletstootherproductsarediscussedseparately.(See"Massivebloodtransfusion",sectionon
'Trauma'and"Useofbloodproductsinthecriticallyill".)

Redistribution/splenomegalyInindividualswithnormalsplenicfunction,approximatelyone
thirdoftheplateletmassisfoundinthespleen,inequilibriumwiththecirculatingplateletpool[11].
Conditionsthatincreasesplenicsizeand/orcausespleniccongestionthroughportalhypertension
(eg,cirrhosis,alcoholicliverdisease)candecreasetheplateletcountwithoutalteringthetotal
plateletmassinthebody(figure1)[11].Severethrombocytopeniaorbleedinginthesettingof
splenomegalyshouldpromptthecliniciantoinvestigateforothercauses.(See"Approachtothe
adultpatientwithsplenomegalyandothersplenicdisorders",sectionon'Causesof
splenomegaly'.)

CAUSESOFTHROMBOCYTOPENIAThepotentialcausesofthrombocytopeniadifferdepending
ontheclinicalsettinginwhichitoccurs.Individualspresentingwithasymptomatic,isolated
thrombocytopeniaaremorelikelytohaveimmunethrombocytopenia(ITP)whereasacutelyill,
hospitalizedpatientswhodevelopthrombocytopeniaaremorelikelytohaveplateletconsumption,
dilution,bonemarrowsuppressionfromsepsis/infection,ordruginducedthrombocytopenia.In
betweentheseextremesareautoimmunedisorders,nutrientdeficiencies,thrombotic
microangiopathies,orinfections,whichmayhavearangeofpresentationsdependingontheseverity
oftheunderlyingcondition.

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Causesofthrombocytopeniaarepresentedinthetable(table2)andinthefollowinglist,orderedfrom
theleastlikelytobesymptomatictothemostacutelyill.However,thepatient'sclinicalstatuscannotbe
usedtoexcludeorconfirmadiagnosis,asmanyofthesecausescanhaveavariableclinical
presentation.

PregnancyMostpregnantwomenhavenormalplateletcounts.Approximately5percent
developincidentalthrombocytopeniaduringpregnancy,alsotermedgestationalthrombocytopenia.
Gestationalthrombocytopeniaismild,asymptomatic,occursduringlategestation,andresolves
spontaneouslyafterdelivery.Thereisnoassociatedriskofbleedingorfetalthrombocytopenia.
Anychangefromroutineobstetricalcareisdiscouraged.(See"Thrombocytopeniainpregnancy".)

Incontrast,iftheplateletcountislessthan70,000/microL,evaluationforalternativeexplanations
ofthrombocytopeniasuchasITPmustbeperformed.(See'Overviewofourapproach'below.)

Severethrombocytopenia,orthrombocytopeniaaccompaniedbyotherfindingsduringpregnancy
(eg,renalinsufficiency,hypertension,microangiopathichemolyticanemia)shouldpromptan
evaluationformoreseriousdisorderssuchasthehemolysis,elevatedliverenzymes,lowplatelet
count(HELLP)syndrome,preeclampsia,orthromboticthrombocytopenicpurpura(TTP).(See
"HELLPsyndrome"and"Thrombocytopeniainpregnancy",sectionon'Preeclampsiawithsevere
features/HELLP'and"Thrombocytopeniainpregnancy".)

ChronicliverdiseaseorhypersplenismIsolatedthrombocytopeniamaybetheinitial
manifestationofchronicliverdiseasewithportalhypertensionandcongestivesplenomegaly
(hypersplenism).Thrombocytopeniaisusuallymildtomoderate(eg,intherangeof60,000to
100,000/microL),andthespleenisoftenpalpablyenlarged.Intheseconditions,thetotalnumber
ofplateletsisnormalthelowplateletcountintheperipheralbloodmerelyrepresentsredistribution
ofagreaterproportionofplateletsintothecongestedspleen.Upto90percentofplateletsmaybe
pooledwithinthespleniccirculationinpatientswithchronicliverdiseaseandhypersplenism,
comparedwithapproximatelyonethirdofplateletsinindividualswithouthypersplenism[11].

Thefrequencyofliverdiseaseasacauseofisolatedthrombocytopeniawasillustratedbya
retrospectivestudyof203patientswithisolatedthrombocytopeniaofunknowncausewho
underwentdiagnosticbonemarrowevaluation[12].Halfofthosewithanormalbonemarrow
evaluationwerefoundtohavecirrhosis.Nonalcoholicsteatohepatitiswasthemostcommoncause
ofcirrhosisinthispopulation(47percent),followedbyalcoholuseandhepatitisCvirusinfection.
Consistentwiththesefindings,thefrequencyofthrombocytopeniainaseriesof354patientswith
apresumptivediagnosisofnonalcoholicfattyliverdiseasewas29percent[13].(See
"Epidemiology,clinicalfeatures,anddiagnosisofnonalcoholicfattyliverdiseaseinadults"and
"Alcoholichepatitis:Clinicalmanifestationsanddiagnosis"and"Hematologiccomplicationsof
alcoholuse".)

ImmunethrombocytopeniaImmunethrombocytopenia(ITP)isacommoncauseofmoderate
toseverethrombocytopeniainanotherwiseasymptomaticadult.Othercelllinesareunaffected
(ie,ITPdoesnotcauseanemiaorleukopenia).ITPiscausedbyantibodymediatedplatelet
destruction.However,antiplateletantibodiesarenotalwaysdetected,andtheirtestingisnot
clinicallyuseful.ApresumptivediagnosisofITPismadewhenthehistory,physicalexamination,
andlaboratorydatadonotsuggestanalternativediagnosis.Onlyacompletebloodcount(CBC)
andreviewoftheperipheralbloodsmeararerequiredhowever,othertestingmaybeusefulto
eliminatesecondarycausesofITP(eg,HIVandhepatitisCtesting)orothernonimmunecauses
ofthrombocytopenia(eg,liverenzymesforpossiblehepaticimpairment).(See"Immune
thrombocytopenia(ITP)inadults:Clinicalmanifestationsanddiagnosis".)
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CongenitalplateletdisordersSomecongenitalplateletdisordersassociatedwith
thrombocytopeniaarediscoveredincidentally.Severalmaybeassociatedwithverylargeplatelets
ontheperipheralbloodsmear(eg,MayHegglinanomaly,BernardSouliersyndrome,Gray
plateletsyndrome).Althoughthesearerareandoftendiagnosedinchildhood,anadult
presentationispossiblesomeindividualscarryamistakendiagnosisofITP.(See"Causesof
thrombocytopeniainchildren",sectionon'Geneticcausesofdefectivethrombopoiesis'and
"Congenitalandacquireddisordersofplateletfunction",sectionon'Inheriteddisordersofplatelet
function'.)

OtherinheritedsyndromesassociatedwiththrombocytopeniaincludeWiskottAldrichsyndrome,
thrombocytopeniawithabsentradius(TAR)syndrome,Alportsyndrome(hereditarynephritis),and
asmallsubsetofpatientswithvonWillebranddisease.Theseconditionsareoftenassociatedwith
otherclinicalfindingsthatmayonlybeappreciatedoncetheunifyingdiagnosisisconsidered.
Althoughtheseconditionsareoftendiagnosedinchildhood,anadultpresentationispossible.
(See"WiskottAldrichsyndrome"and"ClinicalpresentationanddiagnosisofvonWillebrand
disease",sectionon'Type2B'and"Causesofthrombocytopeniainchildren",sectionon'TAR
syndrome'and"Clinicalmanifestations,diagnosisandtreatmentofhereditarynephritis(Alport
syndrome)".)

InfectionThrombocytopeniacanoccurwithavarietyofinfections.Themechanism(s)may
includeimmunemediatedplateletdestruction,bonemarrowsuppression,orplateletconsumption.

ViralThrombocytopeniamayoccurafteranumberofviralinfections(eg,rubella,mumps,
varicella,parvovirus,hepatitisC,andEpsteinBarrvirus).Thrombocytopeniamaybean
incidentalfindingthatresolvesspontaneouslyasthepatientrecovershowever,insome
persistentinfections,suchashepatitisC,thrombocytopeniamayalsopersist.(See
"ExtrahepaticmanifestationsofhepatitisCvirusinfection".)

Themeaslesmumpsrubellavaccinehasbeenassociatedwiththrombocytopeniathis
associationisextremelyrare(ie,<1in30,000forvaccinationversus1in3000forrubella
infection)[14,15].(See"Measles,mumps,andrubellaimmunizationinadults".)

CasereportshavedescribedthrombocytopeniainassociationwithZikavirusinfection[16,17].
(See"Zikavirusinfection:Anoverview".)

HIVHumanimmunodeficiencyvirus(HIV)infectionisarareetiologyofnewlydiscovered
thrombocytopenia.However,sincethrombocytopeniamaybetheinitialmanifestationofHIV
infection,itisappropriatetotestforHIVaspartoftheevaluationofthrombocytopenia[18,19].

HIVcancausethrombocytopeniabyseveralmechanisms,includingdirecttoxicityto
megakaryocytesanITPlikeconditioncalledprimaryHIVassociatedthrombocytopenia
(PHAT)andsecondaryopportunisticinfections(eg,mycobacteriumaviumintracellulare).
Thissubjectisdiscussedindetailseparately.(See"HematologicmanifestationsofHIV
infection:Thrombocytopeniaandcoagulationabnormalities".)

Bacterialinfection/sepsisSepsiscancausethrombocytopeniabydirectbonemarrow
suppression,whichisusuallyaccompaniedbyothercytopeniasasacomponentof
disseminatedintravascularcoagulation(DIC),inwhichitisaccompaniedbycoagulation
abnormalities(eg,prolongedPT,aPTT,lowfibrinogen)fromplateletconsumption
independentofDICorfromincreaseddestructionofplatelets.Patientsaregenerallyacutely

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ill,andtreatmentisdirectedattheunderlyinginfection.(See"Clinicalfeatures,diagnosis,and
treatmentofdisseminatedintravascularcoagulationinadults".)

InfectionwithHelicobacterpylorihasalsobeenassociatedwithimmunethrombocytopenia.
Thismaybesuspectedinpatientswithdyspepsiaorsymptomsofpepticulcerdisease.(See
"Immunethrombocytopenia(ITP)inadults:Initialtreatmentandprognosis",sectionon
'Helicobacterpyloriinfection'and"AcuteandchronicgastritisduetoHelicobacterpylori".)

Thrombocytopeniaisacommonfindingwithotherspecificinfectionsincludingleptospirosis,
brucellosis,anaplasmosis,andothertickborneinfections.(See"Epidemiology,microbiology,
clinicalmanifestations,anddiagnosisofleptospirosis"and"Clinicalmanifestations,diagnosis,
andtreatmentofbrucellosis"and"Humanehrlichiosisandanaplasmosis"and"Borrelia
miyamotoiinfection".)

IntracellularparasitesMalariaandbabesiosiscancausethrombocytopenia,typically
accompaniedbyfeverandhemolyticanemiapatientsmaypresentwithmildillnessorbe
acutelyill.Thecausativeorganismsmaybeseenonreviewoftheperipheralbloodsmear.
(See"Clinicalmanifestationsofmalariainnonpregnantadultsandchildren",sectionon
'Hematologicabnormalities'and"Clinicalmanifestations,diagnosis,treatment,andprevention
ofbabesiosis",sectionon'B.microti'.)

Medications

DruginducedimmunethrombocytopeniaVirtuallyanymedicationcancause
thrombocytopeniabytheoccurrenceofdrugdependent,plateletreactiveantibodies,but
certainagentsaremorecommonlyimplicated.Examplesincludeantibiotics(eg,
sulfonamides,ampicillin,piperacillin,vancomycin,rifampin)olderantiepilepticagents(eg,
carbamazepine,phenytoin),andquinine(table3andtable4).Typically,thrombocytopenia
developswithinhoursofdrugexposureifthepatienthasbeenpreviouslyexposedtothe
drug,orwithinonetotwoweeksofdailyexposuretoanewdrug.Thethrombocytopenia
typicallyresolveswithinfivetosevendaysofdrugdiscontinuation[20].Specifictreatmentis
rarelyrequired.Theauthormaintainsawebsiteofimplicateddrugsat
www.ouhsc.edu/plateletsamorecomprehensivediscussionofdruginduced
thrombocytopeniaispresentedseparately.(See"Druginducedimmunethrombocytopenia".)

HeparininducedthrombocytopeniaHeparininducedthrombocytopeniaisaspecialcase
ofdruginducedthrombocytopeniainwhichantiplateletantibodiescauseplateletactivation,
resultinginanincreasedriskofvenousandarterialthrombosis.

ClinicalfeaturessuggestiveofHITincludenewonsetthrombocytopeniainapatientexposed
toheparinwithintheprior5to10daysaplateletcountdrop>50percentofbaselinevenous
orarterialthrombosisnecroticskinlesionsatsitesofheparininjectionandacutesystemic
reactionsafterintravenousheparinadministration.Treatmentinvolvesimmediate
discontinuationofheparinandadministrationofanonheparinanticoagulant.Evaluationfor
HITandmanagementofpatientswithapresumptiveclinicaldiagnosisofHITarediscussedin
detailseparately.(See"Clinicalpresentationanddiagnosisofheparininduced
thrombocytopenia"and"Managementofheparininducedthrombocytopenia".)

CytotoxicchemotherapyorradiationtherapyCytotoxicchemotherapyagentsand
radiationtherapyinduceapredictable,dosedependentmyelosuppressionthattypically
affectsallbloodcelllines(table5).Whiletherecoveryofbloodcellcountsfollowing

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discontinuationisalsopredictable,occasionalpatientswithunderlyingbonemarrowdisorders
mayhaveaslowerplateletcountriseafterdiscontinuation.

Overthecounterremedies,supplements,foods,andbeveragesThrombocytopeniahas
beenreportedafteringestionofquininecontainingbeverages(eg,tonicwater,bitterlemon)(table
4),aswellasnumerousherbalpreparations[21,22],foods[23,24],andoverthecounter
medicines.Athoroughhistorymayrevealadietarycauseofthrombocytopeniainsomepatients.
Thisissueisdiscussedseparately.(See"Druginducedimmunethrombocytopenia".)

AlcoholAlcoholcancausethrombocytopeniabydirecttoxicitytothebonemarrow,nutrient
deficiencies,orhypersplenismassociatedwithalcoholicliverdisease.Patientsmayberelatively
asymptomaticorillfromcirrhosis.(See"Hematologiccomplicationsofalcoholuse",sectionon
'Thrombocytopenia'.)

MalignancyCancercancausethrombocytopeniaasacomponentofchronicDIC,bonemarrow
infiltration,orthromboticmicroangiopathy.(See"Clinicalfeatures,diagnosis,andtreatmentof
disseminatedintravascularcoagulationinadults",sectionon'CausesofDIC'and"Anemiasdueto
decreasedredcellproduction",sectionon'Leukoerythroblasticanemia'.)

NutrientdeficienciesDeficiencyofnutrientsrequiredforhematopoiesis(eg,folate,vitamin
B12,copper)typicallycausesmildpancytopenia,butisolatedthrombocytopeniamaybeseen.
Patientsmaybeasymptomaticoraffectedbysymptomsofanemiaand/orneurologicfindings.
Thesedeficienciescandevelopinthesettingofcertaindietarypractices(eg,poornutrition,
veganism,excessivezincingestion),byanautoimmunemechanism,orfollowingbariatricorother
gastrointestinalsurgeriesifsupplementationisinadequate(table6).(See"Diagnosisand
treatmentofvitaminB12andfolatedeficiency"and"Copperdeficiencymyeloneuropathy",section
on'Hematological'and"Bariatricsurgery:Postoperativenutritionalmanagement".)

Thromboticmicroangiopathy(TMA)TMAssuchasthromboticthrombocytopenicpurpura
(TTP),hemolyticuremicsyndrome(HUS),anddruginducedTMA(DITMA)arerareinadults,but
mustbeconsideredinanyadultwithmicroangiopathichemolyticanemiaandthrombocytopenia.
(See"ApproachtothepatientwithsuspectedTTP,HUS,orotherthromboticmicroangiopathy
(TMA)".)

PatientswithTTP,HUS,orDITMArarelypresentwiththefullpentadofclinicalfeatures
(microangiopathichemolyticanemia,thrombocytopenia,neurologicfindings,renalinsufficiency,
fever)thatwerecommonintheerabeforeeffectivetreatment.Manypatientshaveonly
thrombocytopeniaandmicroangiopathichemolyticanemia.Acutekidneyinjurysupportsthe
diagnosisofHUSratherthanTTP.

AnacuteepisodeofTTPorHUSmayalsobe"triggered"byanotheracuteillnessandtherefore
mayoccursuddenlyandunexpectedlyinpatientshospitalizedforotherdisorders,suchascardiac
surgeryorpancreatitis[25].(See"PathophysiologyofacquiredTTPandotherprimarythrombotic
microangiopathies(TMAs)".)

BonemarrowdisordersSeveralprimaryhematologicdisorderscausethrombocytopenia
however,thesedisorderstypicallycauseotherabnormalitiesoftheCBC(eg,pancytopenia,
leukocytosis).Suspicionofanyoftheseconditionsshouldprompthematologistinvolvementand
bonemarrowevaluation(see'Additionalevaluation'below).

Myelodysplasticsyndromescausevaryingdegreesofthrombocytopeniainroughlyone
quarterofpatients,butisolatedthrombocytopeniaisrare.(See"Clinicalmanifestationsand
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diagnosisofthemyelodysplasticsyndromes",sectionon'Completebloodcount'.)

Bonemarrowfailuresyndromescancausethrombocytopenia,almostalwaysaccompaniedby
othercytopenias.(See"Aplasticanemia:Pathogenesisclinicalmanifestationsand
diagnosis".)

AcuteleukemiatypicallypresentswithleukocytosisandimmatureWBCsintheperipheral
bloodthrombocytopeniaandanemiaoftenaccompanythesechanges,butthrombocytopenia
israrelyseeninisolation.(See"Clinicalmanifestations,pathologicfeatures,anddiagnosisof
acutemyeloidleukemia".)

Paroxysmalnocturnalhemoglobinuria(PNH)canpresentwithbonemarrowfailure,including
thrombocytopeniathrombosis.(See"Clinicalmanifestationsanddiagnosisofparoxysmal
nocturnalhemoglobinuria"and"Treatmentandprognosisofparoxysmalnocturnal
hemoglobinuria".)

Rheumatologic/autoimmunedisordersSystemiclupuserythematosus(SLE)isassociated
withsecondaryITPinonequartertoonehalfofindividuals.(See"Hematologicmanifestationsof
systemiclupuserythematosusinadults",sectionon'Thrombocytopenia'.)

Theantiphospholipidsyndrome(APS)isanautoantibodymediatedsyndromecharacterizedby
venousorarterialthrombosisand/orpregnancymorbiditystrokeandotherneurologic
complicationsmayoccur.Mildtomoderatethrombocytopeniaisoftenpresent(See"Clinical
manifestationsofantiphospholipidsyndrome".)

Thrombocytopeniamaybeseeninrheumatoidarthritisandmaybeaccompaniedby
splenomegaly(eg,Felty'ssyndrome).(See"Hematologicmanifestationsofrheumatoidarthritis",
sectionon'Neutropenia'.)

OthercausesAdditionalrarecausesofthrombocytopeniaincludevascularconditions
associatedwithplateletdestruction(eg,giantcapillaryhemangioma,largeaorticaneurysms,
cardiopulmonarybypass)(table1)[26].Posttransfusionpurpuraisarareformofimmune
mediatedplateletdestructionfollowingtransfusionofplateletcontainingbloodproducts.(See
"Immunologicbloodtransfusionreactions".)

OVERVIEWOFOURAPPROACHOurapproachtothepatientwithnewlydiscovered,unexplained
thrombocytopeniainvolvesconfirmationofthefindingbyrepeatingthecompletebloodcount(CBC)
andreviewingtheperipheralbloodsmear,obtainingpriorplateletcountsifavailable,andassessing
otherhematologicabnormalities.Thepaceofthesubsequentevaluationandfurthertestingdepends
ontheclinicalpresentation,whichcanrangefromasymptomatictoacutelyill(table7).

ThrombocytopenicemergenciesrequiringimmediateactionCertainpresentationsof
thrombocytopeniaaremedicalemergenciesthatrequireimmediateaction.Theseinclude:

Bleedinginthesettingofseverethrombocytopenia(ie,plateletcount<50,000/microL)
Urgentlyneededinvasiveprocedurewithseverethrombocytopenia
Pregnancywithseverethrombocytopenia
Suspectedheparininducedthrombocytopenia(HIT)
Suspectedthromboticthrombocytopenicpurpura(TTP),hemolyticuremicsyndrome(HUS),or
druginducedthromboticmicroangiopathy(DITMA)
Suspectedacuteleukemia,aplasticanemia,orotherbonemarrowfailuresyndrome

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Theconsultingspecialist(eg,hematologist)canassistwithpatientevaluation,diagnosisand
managementstrategies,includingplatelettransfusions,othermeansofrapidlyraisingtheplatelet
count(eg,intravenousimmuneglobulinforITP,plasmaexchangeforTTP),preventionofadditional
complications(eg,thrombosis),andtreatmentoftheunderlyingcondition.(See'Thrombocytopenia
withbleedingorothersymptoms'belowand'Hematologistreferral/consultation'below.)

InitialquestionsandpaceoftheevaluationWhenapatientpresentswithunexpected
thrombocytopenia,wewanttoknow:

Isthethrombocytopeniareal?
Isthethrombocytopenianew?
Arethereotherhematologicabnormalities?

Confirmationthatthethrombocytopeniaisreal(eg,notalaboratoryerrororaninvitroartifact)isdone
byrepeatingtheCBCandreviewingtheperipheralbloodsmear(orrequestingreview),especiallyifthe
plateletcountdoesnotmakesensewithinthecontextoftheclinicalpicture.(See'RepeatCBC'below
and'Peripheralbloodsmear'below.)

Anewreductioninplateletcountismoreconcerningthanastable,mildlylowcountbecauseit
suggeststhepossibilityofanevolvingcondition.Priorplateletcountsarehelpfulinthisregard,if
available,andtheplateletcountshouldbemonitoredtodeterminethetrendgoingforward,withthe
intervaldependentontheseverityofthrombocytopeniaandotherclinicalfindings.(See'History'below
and'RepeatCBC'below.)

Additionalcluescanalsobeidentifiedfromthebloodsmear(eg,giantplatelets,whicharereadbythe
automatedcounterasredbloodcellsbecauseoftheirsizeorfragmentedredbloodcells,whichare
characteristicofthromboticmicroangiopathy).Otherhematologicabnormalities(eg,anemia,
leukopenia,leukocytosis)generallysuggestamoreseriousdiagnosisthanisolatedthrombocytopenia.
(See'RepeatCBC'belowand'Peripheralbloodsmear'below.)

Anypatientwithunexplainedthrombocytopeniashouldbeseenbyahematologisttodeterminethe
causeandappropriatemanagementtheurgencydependsonthedegreeofthrombocytopeniaand
otherfindings.(See'Hematologistreferral/consultation'below.)

Asymptomatic,incidentalfinding,mildthrombocytopeniaCommondiagnosesfor
asymptomaticoutpatientswithmildthrombocytopeniaincludeimmunethrombocytopenia(ITP),occult
liverdisease,HIVinfection,andmyelodysplasticsyndromes.Congenitalthrombocytopenicconditions,
sometimesmisdiagnosedasITP,mayalsooccur.(See'Causesofthrombocytopenia'above.)

Inapatientwithincidentallydiscoveredasymptomaticthrombocytopeniaandaprobablediagnosisof
ITP,nofurtherevaluationbeyondtheroutinehistory,physicalexamination,CBC,andreviewofthe
peripheralbloodsmear,andtestingforhumanimmunodeficiencyvirus(HIV)andhepatitisCvirus
(HCV)infectionisnecessary.(See'History'belowand'Physicalexamination'belowand'Laboratory
testing'belowand"Immunethrombocytopenia(ITP)inadults:Clinicalmanifestationsanddiagnosis",
sectionon'Preliminaryevaluation'.)

Referraltoahematologisttoconfirmthediagnosisisappropriate.Followingthat,routinemonitoring
canbedonebythepatient'sprimarycarephysician.Antiplateletantibodystudiesarenotroutinely
doneandimagingstudies,andbonemarrowaspirationandbiopsyarenotnecessaryunlessother
abnormalitiesarepresent.(See'Hematologistreferral/consultation'below.)

Thenaturalhistoryofasymptomatic,mildthrombocytopeniawasstudiedprospectivelyin217
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apparentlyhealthyindividualsreferredtoahematologycenterforincidentallydiscoveredplatelet
countsbetween100,000and150,000/microL[27].Atsixmonthsofobservation,23(11percent)had
normalplateletcounts,twodevelopedamyelodysplasticsyndrome(refractoryanemia),andone
developedsystemiclupuserythematosus.Theremaining191individuals(88percent)hadpersistent
plateletcounts<150,000/microLduringthisperiodwithoutothersignsofdiseasebecomingevident
afterfiveyears,most(64percent)hadspontaneousresolutionorpersistentmildthrombocytopenia
withoutdevelopmentofanassociatedcondition,supportingadiagnosisofITP.

ThrombocytopeniawithbleedingorothersymptomsPatientswhopresentwithisolated
thrombocytopeniaandbleeding,manifestedbypetechiae,purpura,andmucosalbleeding(eg,
epistaxis,menorrhagia),haveadifferentdiagnosticspectrum.

Individualswithbleedingwholacksignsofsystemicillnessorotherabnormalitiesofthecomplete
bloodcountarelikelytohavedruginducedthrombocytopeniaorprimaryITP.Thesediagnoses
aremadebasedontheappropriatehistory(eg,drugexposure,bleeding,absenceofotherspecific
symptoms)andlackofotherfindingsonphysicalexamination.Noadditionallaboratorytestingis
needed,withtheexceptionofHIVandHCVtesting.(See'RepeatCBC'belowand'Peripheral
bloodsmear'belowand'HIVandHCVtesting'below.)

Theroleoftestingfordrugdependentantibodiesinpotentialdruginducedthrombocytopeniais
discussedseparately.(See"Druginducedimmunethrombocytopenia",sectionon'Decidewhich
drug(s)tostop'.)

Individualswiththrombocytopeniaandothersymptomshaveabroaderrangeofpotential
diagnoses.Specificdiagnosestoconsiderdependontheotherclinicalfindings.Asexamples:

FeverPossibleinfection,sepsis,disseminatedintravascularcoagulation(DIC)
HepatosplenomegalyPossibleliverdiseasewithhypersplenism,lymphoma
NeurologicfindingsPossibleTTP,HUS,DITMA,vitaminB12deficiency,orcopper
deficiency
LymphadenopathyPossibleinfection,lymphoma,othermalignancy
ThrombosisPossibleHIT,antiphospholipidsyndrome(APS),orparoxysmalnocturnal
hemoglobinuria(PNH)

Theseindividualsshouldhaveadditionallaboratoryevaluationdirectedatthediagnoses
suggestedbytheseothersymptoms.(See'Otherlaboratorytesting'below.)

Acutelyill/intensivecareunitThrombocytopeniaiscommoninacutelyillpatients.Asanexample,
theProphylaxisforThromboembolisminCriticalcareTrial(PROTECT),whichrandomlyassigned
3746patientsinanintensivecareunit(ICU)totreatmentwithunfractionatedheparinorlowmolecular
weightheparinforthromboembolismprophylaxis,foundthattheincidencesofmildthrombocytopenia
(plateletcount100,000to149,000/microL),moderatethrombocytopenia(50,000to99,000/microL),
andseverethrombocytopenia(<50,000/microL)were15,5,and2percent,respectively[1].

A2011systematicreviewofthrombocytopeniaintheICU(conductedbeforethePROTECTtrial)
reportedthrombocytopeniain8to68percentatthetimeofICUadmissionandnewonset
thrombocytopeniaduringtheICUstayin13to44percent[28].Thrombocytopeniawascorrelatedwith
highseverityillness,sepsis,andorgandysfunction.

Predictorsofdevelopingthrombocytopeniainacohortof145patientsinamedicalICUincluded
disseminatedintravascularcoagulation(DIC),cardiopulmonaryresuscitation,andorganfailureat

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admission[29].InthePROTECTtrial,whichincludedmedicalandsurgicalICUpatients,predictorsof
thrombocytopeniaincludedahigherAPACHEIIscore(calculator1),surgicaldiagnosis,liver
dysfunction,receiptofinotropesorvasopressorsintheprecedingthreedays,renalreplacement
therapyintheprecedingthreedays,anddevelopmentofHIT[1].

Themostcommoncauseofnewonsetthrombocytopeniainacohortof329medicalandsurgicalICU
patientswassepsis,accountingforonehalfofthecases[30].Morethanonecauseof
thrombocytopeniawasfoundin26percent.Thefrequencyofspecificcausesofthrombocytopenia
includedthefollowing:

Sepsis,all(48percent)
Sepsiswithdocumentedbacteremia(28percent)
Liverdisease/hypersplenism(18percent)
OvertDIC(14percent)
Unknowncause(14percent)
Infection,other(11percent)
Primaryhematologicdisorder(9percent)
Medications,noncytotoxic(9percent)
Medications,cytotoxic(7percent)
Massivetransfusion(7percent)
Othercauses(7percent)
Alcoholism(5percent)

Basedonthisspectrumoffindings,weobtainlaboratorytestingforDIC,sepsis,andliverdiseaseusing
coagulationstudies,liverfunctiontests,andculturesofbloodandbodyfluidsincriticallyillpatientswith
thrombocytopenia.(See"Clinicalfeatures,diagnosis,andtreatmentofdisseminatedintravascular
coagulationinadults"and"Hemostaticabnormalitiesinpatientswithliverdisease".)

Itisalsoimportanttoevaluatethepossibilityofrareyetlifethreateningconditionssuchasheparin
inducedthrombocytopenia(HIT),thromboticthrombocytopenicpurpura(TTP),druginducedimmune
thrombocytopenia(DITP),posttransfusionpurpura(PTP),primaryimmunethrombocytopenia(ITP),
andacuteleukemia[31,32].Bonemarrowevaluationisappropriateifthrombocytopeniaissevereand
othercelllinesareabnormal.Forpatientswithmoderatetoseverethrombocytopenia,athorough
reviewofmedicationsthatwerestartedinthetwoweekspriortodevelopmentofthrombocytopenia
shouldbeundertaken,and,ifDITPissuspected,theresponsiblemedication(s)shouldbe
discontinued,withclosemonitoringofplateletcountrecovery[33].HITisanuncommoncauseof
thrombocytopeniaintheintensivecareunit[34].However,patientswithaclinicalsuspicionofHIT
shouldundergoHITantibodytesting.(See"Druginducedimmunethrombocytopenia"and"Clinical
presentationanddiagnosisofheparininducedthrombocytopenia",sectionon'Evaluation'and
"ApproachtothepatientwithsuspectedTTP,HUS,orotherthromboticmicroangiopathy(TMA)".)

Adverseoutcomesgenerallycorrelatewiththeseverityofthrombocytopenia.Thedegreeof
thrombocytopeniacorrelatedwiththeriskofbleedinginthePROTECTtrial(adjustedhazardratiosfor
mild,moderate,andseverethrombocytopeniawere1.96,3.52,and3.54,respectively)[1].Moderate
andsevere(butnotmild)thrombocytopeniaalsocorrelatedwithanincreasedlengthofICUstayand
ICUdeath[1].

Additionaldiagnosticconsiderationsinacutelyillpatientswithpancytopenia(ie,leukopenia,anemia,
andthrombocytopenia),suchashemophagocyticlymphohistiocytosis(HLH),arepresentedseparately.
(See"Clinicalfeaturesanddiagnosisofhemophagocyticlymphohistiocytosis"and"Aplasticanemia:
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Pathogenesisclinicalmanifestationsanddiagnosis".)

HISTORYThereisnosubstituteforathoroughpatienthistoryfordeterminingwhetherother
conditionsarepresentthatmayexplainthrombocytopenia.Certainconditionsassociatedwith
thrombocytopeniaareobviousandcanbeimmediatelyrecognizedbytheclinician,whileothersmay
requirespecificquestioning.Inanacutelyillpatientwhocannotprovideahistory,thisinformation
shouldbeobtainedfromfamilymembersand/orotherclinicianscaringforthepatient.

Ahelpfulhistoryincludesthefollowing:

Priorplateletcounts,ifavailable,becauseastableplateletcountislessconcerningthananewor
decreasingcount.

Familyhistoryofbleedingdisordersand/orthrombocytopenia

Historyofbleeding(eg,petechiae,ecchymoses,epistaxis,gingivalbleeding,hematemesis,
melena,menorrhagia)

MedicationexposuresItisimportanttoincludenewprescriptions,medicationsthatareonly
takenintermittently,overthecountermedicines(eg,aspirin,nonsteroidalantiinflammatory
drugs),herbalremedies,andmedicinesprescribedforotherfamilymembersorfriendsthatthe
patientmayhavetaken(table3).

Ingestionofquininecontainingbeveragesshouldbeaddressedspecifically,duetothestrong
associationofquinineexposurewiththrombocytopenia(table4).Forhospitalizedpatients,one
mustreviewthehospitalchart,nursingnotes,bedsideflowsheets,andanesthesiarecords.
Relevantmedicinesmayalsobecontainedinmaterialsusedinsurgery(eg,vancomycinmixed
intojointreplacementcement)[35].Thetimingofonsetofclinicalbleedingorfirstrecognitionof
thethrombocytopeniawithuseofmedicationsshouldbeexploredindepthsinceitmayfocus
attentiononthemostlikelyagent(s),especiallyinindividualsreceivingmultiplemedications.

Specialattentionshouldbepaidtoadministrationofheparininhospitalizedorrecentlydischarged
patientsduetothepossibilityofHIT,althoughthisisrare.Thisincludesunfractionatedorlow
molecularweight(LMW)heparin(eg,enoxaparin,dalteparin,tinzaparin,nadroparin),andheparin
flushesinvascularaccesslinesorexposureduringsurgery.Incontrast,wearenotawareofan
associationofthrombocytopeniawithtargetspecificanticoagulants(eg,directthrombininhibitors,
factorXainhibitors).

Infectiousexposures,includingrecentinfections(viral,bacterial,rickettsial)orlivevirus
vaccinationrecenttraveltoanareaendemicformalaria,denguevirus,leptospirosis,
meningococcemia,ratbitefever,rickettsialinfections,hantavirus,andviralhemorrhagicfevers
(eg,Ebola,Lassafever)andriskfactorsforHIVinfection[36,37].

Dietarypracticesthatcouldcausenutrientdeficiencies(eg,veganism,vegetarianism,zinc
ingestion)

Othermedicalconditions,includinghematologicdisordersrheumatologicdiseasesbariatric
surgeryorpoornutritionalstatusbloodproducttransfusionororgantransplantation[38]

PHYSICALEXAMINATIONThephysicalexaminationshouldfocusonsignsofbleeding,andthe
presenceoflymphadenopathyorhepatosplenomegaly,whichmaybesignsofanunderlyingcondition
responsibleforthethrombocytopenia.Signsofthrombosismayalsosuggestadifferentspectrumof
potentialcausesofthrombocytopenia.(See'Whentoworryaboutthrombosis'above.)
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SkinandothersitesofbleedingBleedingintotheskinisoneofthemostcommonfindingsin
thrombocytopenia.Ofnote,thrombocytopenicbleedingdiffersfromthebleedingseeninindividuals
withcoagulationabnormalities(table8).Patientswithbleedingduetothrombocytopeniamayhave
petechiae,purpura,orfrankmucosalbleeding.

Petechiaearepinheadsized,red,flat,discretelesionsoftenoccurringincropsindependentareas
(picture2andpicture3).Petechiaearecausedbyredbloodcellextravasationfromcapillaries
theyareasymptomatic,nontender,nonpalpable,anddonotblanchunderpressure.Theyare
mostdenseindependentareaswherethehydrostaticpressureonthesmallsuperficialvesselsis
greatest(eg,feetandanklesinambulatorypatientspresacralareainbedriddenpatients).
Petechiaearenotfoundonthesoleofthefoot,wherethevesselsareprotectedbythestrong
subcutaneoustissue.Petechiaeandotherlesionsshouldbenoted,especiallyinthedependent
partsofthebody.

Purpurareferstopurplishdiscolorationoftheskincausedbyconfluentpetechiae.Drypurpura
referstopurpurainskinwetpurpurareferstomucosalpurpura,inframeBofthepicture(picture
2).Itisgenerallythoughtthatwetpurpuraisaprognosticsignforpotentiallymoreserious
hemorrhage.Palpablepurpuraisnottypicalofthrombocytopeniaandsuggestsanunderlying
vascularorinflammatorydisorder.(See"Evaluationofadultswithcutaneouslesionsofvasculitis".)

Ecchymoses(bruises)arenontenderareasofbleedingintotheskin,usuallyassociatedwith
multiplecolorsduetothepresenceofextravasatedblood(red,purple)andbreakdownproductsof
hemepigment(green,orange,yellow).Ecchymoticlesionscharacteristicallyaresmall,multiple,
andsuperficial.Theymaydevelopwithoutnoticeabletraumaanddonotspreadintodeeper
tissues.

Ofnote,petechiaeandpurpuradifferfromsmalltelangiectasias,angiomas,andvasculiticpurpura
(picture4).

Itcanbehelpfultodocumenttheextentofskinlesions(eg,markwithapen)inordertoidentifynew
lesionsand/orexpansionofexistinglesions,whichmaysignifypersistentorworsening
thrombocytopenia,orraiseadditionalconcernsaboutincreasedbleedingrisk.

Othersitesofbleeding(eg,occultbloodinthestool)requireappropriateevaluationandtreatment,
regardlessofthecauseofthrombocytopenia.(See"Evaluationofoccultgastrointestinalbleeding".)

Liver,spleen,lymphnodesTheliverandspleenshouldbepalpatedfortendernessand
enlargement.Splenomegalycanbesignofliverdisease,lymphoma,orotherhematologiccondition
splenomegalyofanyetiologymaycausemildthrombocytopenia.(See"Approachtotheadultpatient
withsplenomegalyandothersplenicdisorders".)

Lymphadenopathyinapatientwiththrombocytopeniamaysuggestinfection,lymphoma,orother
malignancy.

Focal,tenderlymphnodeenlargementistypicaloflocalizedbacterialinfection.(See"Evaluation
ofperipherallymphadenopathyinadults",sectionon'Localizedlymphadenopathy'.)

GeneralizedlymphadenopathymaybeassociatedwithacuteHIVinfection,inwhichitistypically
nontenderandinvolvesaxillary,cervical,andoccipitalnodes.(See"AcuteandearlyHIVinfection:
Clinicalmanifestationsanddiagnosis",sectionon'Adenopathy'.)

Lymphadenopathymaybeassociatedwithotherinfectious,malignant,autoimmune,and

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inflammatoryconditions.(See"Evaluationofperipherallymphadenopathyinadults",sectionon
'Generalized'.)

LABORATORYTESTINGReviewofthecompletebloodcount(CBC)andperipheralbloodsmear
areessentialinapatientwithunexpectedthrombocytopenia.Plateletclumpingsuggeststhepossibility
ofpseudothrombocytopenia.

RepeatCBCAplateletcountthatdoesnotmakesensewithinthecontextoftheclinicalfindings
shouldberepeatedbeforeextensiveevaluationisundertaken.

Forsymptomaticpatients(eg,signsofbleeding)orthosewithseverethrombocytopenia(ie,
<50,000/microL),suchretestingshouldbeperformedimmediately.

Forasymptomaticpatients(eg,nonbleeding,noassociatedcomorbidities)withmoderate
thrombocytopenia(ie,50,000to100,000/microL),testingmayberepeatedinonetotwoweeks,
providedthepatientisadvisedtoreportimmediatelyanychangesinclinicalstatusorbleeding
duringthisinterval.

Foroutpatientswithisolatedmildthrombocytopenia(ie,100,000to149,000/microL),testingmay
berepeatedinoneormoremonths,asasmallpercentofthesepatientswilldevelopanormal
plateletcountwithobservationonly.Anexceptionisapatientrecentlystartedonanew
medication,newclinicalfindings,orotherabnormalitiesontheCBC,becausemild
thrombocytopeniamaybeasignofanevolvingdisorder(eg,druginducedorheparininduced
thrombocytopenia,druginducedthromboticmicroangiopathy).

Thedefaultdiagnosisinanasymptomaticpatientwithisolatedthrombocytopenia(ie,nobleedingor
signsofotheracuteillness,normalvaluesontheremainderoftheCBC,unremarkableperipheral
bloodsmear)isprimaryimmunethrombocytopenia(ITP),providedothercausesofthrombocytopenia
havebeeneliminated(eg,HIVinfection,druginducedthrombocytopenia,myelodysplasia).

Incontrast,thediagnosticpossibilitiesaremoreextensiveforasymptomaticpatientand/orapatient
withthrombocytopeniainthesettingofotherhematologicabnormalities.

Combinedanemiaandthrombocytopeniamayoccuriftherehasbeenlongstandingbleeding(eg,
gastrointestinal).Combinedanemiaandthrombocytopeniaalsoraisesthepossibilityofsystemic
disorders.

Sepsiswithdisseminatedintravascularcoagulation(DIC)
TTP,HUS,orDITMA
Autoimmunedisorders(eg,Felty'ssyndrome)
Nutrientdeficiencies(eg,folate,vitaminB12,copper)
Infections
Bonemarrowdisorders(eg,myelodysplasticsyndromes,leukemia,bonemarrowinfiltration
bymalignancy

Combinedleukocytosisandthrombocytopeniaraisethepossibilityofinfection,chronic
inflammation,andmalignancy.

Combinedleukopenia,anemia,andthrombocytopenia(ie,pancytopenia)isdiscussedindetail
separately.(See"Clinicalmanifestationsanddiagnosisofthemyelodysplasticsyndromes".)

PeripheralbloodsmearReviewoftheperipheralbloodsmearisusedtoexclude

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pseudothrombocytopenia(eg,falselylowplateletcountduetoplateletclumping)andtoevaluate
morphologicabnormalitiesofbloodcellsthatcouldbeusefulindeterminingthecauseof
thrombocytopenia.

Asanexample,giantplatelets(picture5)maysuggestacongenitalplateletdisorder(eg,MayHegglin
anomaly,BernardSouliersyndrome[BSS])thesemaybecountedasredbloodcellsbysome
automatedcounters.(See"Congenitalandacquireddisordersofplateletfunction",sectionon'Giant
plateletdisorders'.)

PseudothrombocytopeniaThepossibilityofpseudothrombocytopenia(ie,falselylowplatelet
count)shouldbeeliminatedbeforeanextensiveevaluationisundertaken.Pseudothrombocytopenia
canoccurinanumberofsettings,allofwhichcanbeidentifiedbyreviewoftheperipheralbloodsmear
and/orrepeatingtheCBCusinganonEDTAanticoagulant:

Incompletelymixedorinadequatelyanticoagulatedsamplesmayformaclotthattrapsplateletsin
thecollectiontubeandpreventsthemfrombeingcounted.

ExposureofsomepatientsamplestotheEDTAanticoagulantinthecollectiontubecaninduce
plateletclumps(picture6)orplateletrosettesaroundwhitebloodcells(WBCs).Thesemaybe
countedbyautomatedcountersasleukocytesratherthanplatelets.

Approximately0.1percentofindividualshaveEDTAdependentagglutininsthatcaninduce
plateletclumping.Thisisthoughttoresultfroma"naturallyoccurring"plateletautoantibody
directedagainstaconcealedepitopeonplateletmembraneglycoprotein(GP)IIb/IIIathat
becomesexposedbyEDTAinduceddissociationofGPIIb/IIIa[3945].

Onoccasion,plateletsmayrosettearoundWBCs(eg,neutrophils,monocytes,lymphoma
cells)[4650].Thisphenomenonhasalsobeencalled"plateletsatellitism."Inonecase,this
resultedfromthepresenceofanEDTAdependentantibodywithdualreactivityagainstGP
IIb/IIIaandtheneutrophilFcgammareceptorIII[49].

Ifplateletclumpingisobserved,theplateletcountisrepeatedusingheparinorsodiumcitrateas
ananticoagulantinthecollectiontube.Ifcitrateisused,theplateletcountshouldbecorrectedfor
dilutioncausedbytheamountofcitratesolutionnosuchcorrectionisneededforheparin.
Alternatively,fresh,nonanticoagulatedbloodcanbepipetteddirectlyintoplateletcountingdiluent
fluid.

RBCandWBCabnormalitiesAbnormalRBCandWBCmorphologiesmaysuggestaspecific
condition.(See"Evaluationoftheperipheralbloodsmear".)

Examplesincludethefollowing:

Schistocytes(picture7)suggestamicroangiopathicprocess(eg,DIC,TTP,HUS,DITMA).
NucleatedRBCs(picture8),andHowellJollybodies(picture9),maybeseenpostsplenectomyor
occasionallyinpatientswithpoorsplenicfunction.
Spherocytes(picture10andpicture11)suggestimmunemediatedhemolyticanemiaorhereditary
spherocytosis.
Leukoerythroblasticfindings(picture12),teardropcells(picture13),nucleatedRBCs,orimmature
granulocytessuggestaninfiltrativeprocessinthebonemarrow
Leukocytosiswithapredominanceofbands(leftshift)and/ortoxicgranulationssuggestinfection
(picture14).
ImmatureWBCs(eg,myeloblasts)(picture15)ordysplasticWBCs(picture16)suggestleukemia
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ormyelodysplasia.
Multilobed/hypersegmentedneutrophils(ie,>5lobes)(picture17)suggestamegaloblastic
process(eg,B12/folate/copperdeficiency).

HIVandHCVtestingThrombocytopeniahasbeenidentifiedasanimportant"indicatorcondition"
forHIVinfection[18].Thus,adultswithnewthrombocytopeniashouldhaveHIVtestingifnotdone
recently.(See"HematologicmanifestationsofHIVinfection:Thrombocytopeniaandcoagulation
abnormalities",sectionon'Incidenceandcausesofthrombocytopenia'and"Screeninganddiagnostic
testingforHIVinfection".)

ThrombocytopeniamayalsobeseenwithhepatitisCvirus(HCV)infectiontestingisappropriatefor
adultswiththrombocytopeniaifnotdonerecently.(See"ScreeningforchronichepatitisCvirus
infection".)

OtherlaboratorytestingAsidefromthetestingmentionedabove(CBC,reviewofperipheral
smear,HIVandHCVtesting),noadditionallaboratorytestingisabsolutelyrequiredinapatientwith
isolatedthrombocytopenia.However,additionaltestingmaybewarrantedinpatientswithother
findings.

Examplesoffindingsthatmaytriggerotherlaboratorytestingincludethefollowing:

Symptomsorfindingsofsystemicautoimmunedisorders(eg,systemiclupuserythematosus
[SLE],antiphospholipidsyndrome[APS])mayprompttestingforantinuclearantibodiesoranti
phospholipidantibodies,respectively.Wedonottestfortheseinpatientswithisolated
thrombocytopeniaandnosignsorsymptomssuggestiveofSLEorAPS.

Findingsofliverdiseaseshouldpromptmeasurementsofhepaticenzymesandpossiblytestsof
liversyntheticfunction(eg,albumin,coagulationtesting),dependingontheseverityoftheliver
disease.(See"Liverbiochemicalteststhatdetectinjurytohepatocytes"and"Testsoftheliver's
biosyntheticcapacity(eg,albumin,coagulationfactors,prothrombintime)".)

ThrombosisshouldpromptconsiderationofDIC,heparininducedthrombocytopenia(HIT),and
APS.Dependingonthesiteofthrombosisandotherhematologicfindings,paroxysmalnocturnal
hemoglobinuria(PNH)mayalsobeaconsideration.Testingfortheseconditionsisdiscussed
separately.(See"Clinicalpresentationanddiagnosisofheparininducedthrombocytopenia"and
"Diagnosisofantiphospholipidsyndrome"and"Clinicalfeatures,diagnosis,andtreatmentof
disseminatedintravascularcoagulationinadults"and"Treatmentandprognosisofparoxysmal
nocturnalhemoglobinuria".)

Microangiopathicchangesontheperipheralsmearshouldpromptcoagulationtesting(eg,PT,
aPTT,fibrinogen)andmeasurementofserumlactatedehydrogenase(LDH)andrenalfunctionto
evaluateforDIC,TTP,orHUSwithsubsequentevaluationbasedontheresults.(See'Peripheral
bloodsmear'aboveand"Approachtotheadultpatientwithanemia"and"Clinicalfeatures,
diagnosis,andtreatmentofdisseminatedintravascularcoagulationinadults"and"Approachtothe
patientwithsuspectedTTP,HUS,orotherthromboticmicroangiopathy(TMA)".)

ADDITIONALEVALUATION

Hematologistreferral/consultationReferraltoahematologistisappropriatetoconfirmanynew
diagnosisofathrombocytopenicconditionortodeterminethecauseofanyunexplained
thrombocytopenia.Theurgencyofreferraldependsonthedegreeofthrombocytopeniaandother
abnormalities,andthestabilityofthefindings.
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Inhospitalizedpatients,someconditionsaremedicalemergenciesthatrequireimmediateaction.Early
hematologistinvolvementindiagnosisandmanagementisappropriateforthefollowing:

Suspectedthromboticthrombocytopenicpurpura(TTP)orhemolyticuremicsyndrome(HUS).
(See"ApproachtothepatientwithsuspectedTTP,HUS,orotherthromboticmicroangiopathy
(TMA)".)

Suspectedheparininducedthrombocytopenia(HIT).(See"Clinicalpresentationanddiagnosisof
heparininducedthrombocytopenia".)

Suspectedhematologicmalignancy(eg,acuteleukemia),aplasticanemia,orotherbonemarrow
failuresyndrome.(See"Clinicalmanifestations,pathologicfeatures,anddiagnosisofacute
myeloidleukemia"and"Aplasticanemia:Pathogenesisclinicalmanifestationsanddiagnosis".)

Theconsultinghematologistcanalsoassistindiagnosisandmanagementofpatientswithsevere
thrombocytopenia(ie,plateletcount<50,000/microL)whohaveseriousbleedingorrequireanurgent
invasiveprocedure,andinpregnantwomenwithseverethrombocytopenia,regardlessofthecause.

BonemarrowevaluationBonemarrowevaluation(aspirateandbiopsy)isnotrequiredinall
patientswiththrombocytopenia.However,itmaybehelpfulinsomepatientsifthecauseof
thrombocytopeniaisunclear,orifaprimaryhematologicdisorderissuspected.Apossibleexception
maybeaclinicalpictureconsistentwithanutrientdeficiencyinwhichabonemarrowwouldonlybe
neededifadeficiencycouldnotbedocumented,orifthehematologicfindingsdidnotresolveupon
nutrientrepletion.

Thefollowingbonemarrowfindingsmaybehelpful:

Normalorincreasednumbersofmegakaryocytessuggeststhatthethrombocytopeniaisdue,at
leastinpart,toaconditionassociatedwithplateletdestruction(eg,druginducedimmune
thrombocytopenia).(See"Druginducedimmunethrombocytopenia",sectionon'Mechanismsof
DITP'.)

Decreasedmegakaryocytenumbers,alongwithoveralldecreasedorabsentcellularity(picture18
andpicture19),isconsistentwithdecreasedbonemarrowproductionofplatelets,asinaplastic
anemia.(See"Aplasticanemia:Pathogenesisclinicalmanifestationsanddiagnosis".)

Inrarecases,severereductionorabsenceofmegakaryocyteswithnootherabnormalities(also
calledacquiredamegakaryocyticthrombocytopeniaoracquiredpuremegakaryocyticaplasia)may
occur.ThisfindingismostoftenreportedinpatientswithSLE,andistypicallyduetoan
autoantibodydirectedagainstthethrombopoietinreceptor.(See"Hematologicmanifestationsof
systemiclupuserythematosusinadults",sectionon'Thrombocytopenia'and"Biologyand
physiologyofthrombopoietin",sectionon'Thrombocytopeniaduetoantithrombopoietin
antibody'.)

MegaloblasticchangesintheRBCandgranulocyticseriessuggestanutrientdeficiency(eg,
vitaminB12,folate,copper)(picture20),whiledysplasticchangessuggestamyelodysplastic
disorder(picture21andpicture22).(See"Clinicalmanifestationsanddiagnosisofthe
myelodysplasticsyndromes".)

Granulomata,increasedreticulinorcollagenfibrosis(picture23andpicture24),orinfiltrationwith
malignantcells(picture25)establishesthediagnosisofbonemarrowinvasion,especiallywhena
leukoerythroblasticbloodpictureisalsopresent.(See"Evaluationoftheperipheralbloodsmear",

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sectionon'Leukoerythroblasticsmear'.)

GENERALMANAGEMENTPRINCIPLESManagementofspecificthrombocytopenicdisorders(ie,
oncethediagnosisismade)isdiscussedinseparatetopicreviews.However,therearesomegeneral
managementprinciplesthatapplytoallpatientswiththrombocytopeniaregardlessofthecause,and
forwhichquestionsmayarisebeforeadiagnosishasbeenestablished.

ActivityrestrictionsPatientswhoareotherwisehealthyandhavenomanifestationsof
petechiaeorpurpuramaynotrequireactivityrestrictions.

Individualconsiderationsapplytoparticipationincertainactivities.Asanexample,individualswith
moderatetoseverethrombocytopenia(<50,000/microL)shouldnotparticipateinextremeathletics
suchasboxing,rugby,andmartialarts.However,norestrictionsarenecessaryforusualactivities.
Excessivemandatedrestrictionsaremorelikelytodecreasetheinformationthepatientprovides
tothephysicianthantoreducethepatientsactivities.

AntiplateletmedicationsandoverthecounterremediesPatientsshouldbeeducated
aboutwhichmedicationsandnonprescriptionremediesinterferewithplateletfunction(eg,aspirin,
nonsteroidalantiinflammatorydrugs,ginkgobiloba).Ingeneral,theseagentsareavoidedunless
thereisaspecificindicationforwhichequivalentalternativesarelacking.(See"Clinicaluseof
ginkgobiloba".)

However,thrombocytopeniabyitselfdoesnotprotectagainstvenousorarterialthrombosis,and
appropriateuseofthromboprophylaxisoranticoagulantsshouldnotbewithheldfromapatient
withmildtomoderatethrombocytopenia(eg,>50,000/microL)ifitisindicated(eg,
postoperatively).Forpatientswithmoreseverethrombocytopenia,decisionsaremadeonacase
bycasebasisregardingtherisksofbleedingandbenefitsofanticoagulation.

SafeplateletcountforinvasiveproceduresMostplateletcountthresholdsforinvasive
proceduresarebasedonweakobservationalevidenceatbest.Ingeneral,procedureswitha
greaterriskofbleedingareperformedathigherplateletcounts.Whilethereissomeflexibilityin
individualcircumstances,anesthesiologistsandsurgeonsperformingtheseprocedureswillhave
thelastword.Alistingofgeneralguidelinesusedfordifferentproceduresispresentedseparately.
(See"Clinicalandlaboratoryaspectsofplatelettransfusiontherapy",sectionon'Preparationfor
aninvasiveprocedure'.)

Optimalmethodsforraisingtheplateletcountinpreparationforaninvasiveproceduredependon
theunderlyingcondition(eg,corticosteroidsorintravenousimmuneglobulin(IVIG)for
presumptiveITPplatelettransfusionformyelodysplasticsyndromes).Theseapproachesare
discussedindetailinseparatetopicreviews.

Individualswithimpairedplateletfunctionmayrequireplatelettransfusionsdespiteadequate
plateletcounts,dependingontheprocedure.Attentionshouldalsobepaidtocorrecting
coagulationabnormalitiesifpresent.

EmergencymanagementofbleedingUrgentmanagementofcriticalbleedinginthesettingof
severethrombocytopeniarequiresimmediateplatelettransfusion,regardlessoftheunderlying
cause.(See"Clinicalandlaboratoryaspectsofplatelettransfusiontherapy",sectionon'Actively
bleedingpatient'.)

SUMMARYANDRECOMMENDATIONS

9
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Thrombocytopenia(ie,plateletcount<150,000/microL[150x109/L])maybeassociatedwitha
varietyofconditions,withassociatedrisksthatrangefromlifethreateningtonone.Wearemost
concernedaboutspontaneousbleedingwithcounts<10,000/microL,andsurgicalbleedingwith
counts<50,000/microL.Rarely,thrombocytopeniaisassociatedwithariskofthrombosisrather
thanbleeding.(See'Definitionsandareasofconcern'above.)

Thepotentialcausesofthrombocytopeniadifferdependingontheclinicalsettinginwhichitoccurs
(table7).(See'Causesofthrombocytopenia'aboveand'Overviewofourapproach'above.)

Severethrombocytopeniawithbleedingandcertaincausesofthrombocytopenia(suspected
heparininducedthrombocytopenia[HIT],thromboticthrombocytopenicpurpura[TTP],
hemolyticuremicsyndrome[HUS],druginducedthromboticmicroangiopathy[DITMA],or
bonemarrowfailuresyndromewithseverepancytopenia)aremedicalemergenciesthat
requireimmediateaction.(See'Thrombocytopenicemergenciesrequiringimmediateaction'
above.)

Inasymptomaticoutpatientswiththrombocytopenia,commondiagnosesincludeimmune
thrombocytopenia(ITP),occultliverdisease,HIVinfection,andmyelodysplasticsyndromes.
Congenitalthrombocytopenias(sometimesmisdiagnosedasITP)mayalsooccur(table2).
(See'Asymptomatic,incidentalfinding,mildthrombocytopenia'above.)

Inpatientswithbleedingwholacksignsofsystemicillnessorotherabnormalitiesofthe
completebloodcount(CBC),druginducedthrombocytopenia(table3)orprimaryITPare
likelydiagnoses.(See'Thrombocytopeniawithbleedingorothersymptoms'above.)

Inpatientswithotherclinicalfindings,causesofthrombocytopeniaincludeinfection,sepsis,
disseminatedintravascularcoagulation(DIC),druginducedthrombocytopenia,HIT,liver
disease,lymphoma,othermalignancies,nutrientdeficiencies(vitaminB12,folate,copper),
TTPorHUS,antiphospholipidsyndrome(APS),andparoxysmalnocturnalhemoglobinuria
(PNH).(See'Thrombocytopeniawithbleedingorothersymptoms'above.)

Inacutelyillpatients,commoncausesofnewonsetthrombocytopeniaincludesepsis,DIC,
anddruginducedthrombocytopenia(table1).Manypatientsintheintensivecareunitwith
thrombocytopeniahavemorethanonecause.(See'Acutelyill/intensivecareunit'above.)

WeconfirmthrombocytopeniabyrepeatingtheCBCandreviewingtheperipheralbloodsmear
obtainpriorplateletcounts,ifavailable,andassessotherhematologicabnormalities.Thepaceof
thesubsequentevaluation,furthertesting,andhematologistconsultationdependsontheclinical
presentation,whichcanrangefromasymptomatictoacutelyill.(See'Overviewofourapproach'
aboveand'Initialquestionsandpaceoftheevaluation'above.)

Thehistoryshouldfocusonpriorplateletcounts,familyhistory,bleeding,medications(table3),
overthecounterremedies(table4),infectiousexposures,dietarypractices,andothermedical
conditions(eg,hematologicdisorders,rheumatologicconditions,surgery,transfusion).The
physicalexaminationshouldevaluatebleeding,lymphadenopathy,hepatosplenomegaly,
thrombosis,andorganinvolvement.(See'History'aboveand'Physicalexamination'above.)

NoadditionallaboratorytestingbesidestheCBCandperipheralbloodsmearisabsolutely
requiredinapatientwithisolatedthrombocytopenia.Adultswithnewthrombocytopeniashould
haveHIVandHCVtestingifnotdonerecently.Additionallaboratorytestingmaybewarrantedin
patientswithotherfindings.(See'Laboratorytesting'above.)

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Hematologistconsultationisappropriatetoconfirmanewdiagnosisorifthecauseof
thrombocytopeniaisunclear.Theurgencyofreferraldependsonthedegreeofthrombocytopenia
andotherabnormalities,andthestabilityofthefindings.Inhospitalizedpatients,earlyhematology
involvementisappropriateforindividualswithsuspectedTTP,HUS,HIT,andsomehematologic
malignancies(eg,acuteleukemia).(See'Hematologistreferral/consultation'above.)

Bonemarrowevaluationisnotrequiredinallpatientswiththrombocytopeniahowever,itmaybe
helpfulinsomepatientsifthecauseofthrombocytopeniaisunclear,orifaprimaryhematologic
disorderissuspected.(See'Bonemarrowevaluation'above.)

Managementofpatientswiththrombocytopeniadependsontheunderlyingdiagnosis.General
principlesthatapplytoallpatientsincludeavoidanceofmedicationsthatinterferewithplatelet
functionunlessalternativesareunavailablecoordinationwithanesthesiologistsandsurgeons
beforeinvasiveprocedures,andcorrectionofcoagulationabnormalities.Activityrestrictionsare
oftennotneeded.(See'Generalmanagementprinciples'aboveand"Clinicalandlaboratory
aspectsofplatelettransfusiontherapy".)

Thrombocytopeniainneonatesandchildren,andthrombocytopeniaduringpregnancyare
discussedseparately.(See"Causesofneonatalthrombocytopenia"and"Causesof
thrombocytopeniainchildren"and"Thrombocytopeniainpregnancy".)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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Topic6680Version41.0

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GRAPHICS

Majorcausesofdisseminatedintravascularcoagulation

EventsthatinitiateDIC
SepticemiaGramnegativeandGrampositive

Crushinjuryorcomplicatedsurgery

Severeheadinjury

Cancerprocoagulant(Trousseau'ssyndrome)

Acuteleukemia,especiallypromyelocytic

Complicationsofpregnancy
Amnioticfluidembolism
Abruptioplacentae
HELLPsyndrome
Eclampsiaandseverepreeclampsia
Septicabortion

Amphetamineoverdose

Gianthemangioma(KasabachMerrittsyndrome)

Abdominalaorticaneurysm

Peritoneovenousshunt

Acutehemolytictransfusionreaction(ABOincompatibility)

Paroxysmalnocturnalhemoglobinuria

Snakeandvipervenoms

Liverdisease
Fulminanthepaticfailure
Reperfusionafterlivertransplantation

Heatstroke

Burns

Purpurafulminans

EventsthatcomplicateandpropagateDIC
Shock

Complementpathwayactivation

Graphic58104Version3.0

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Bonemarrowmegakaryocytes

Bonemarrowaspirateshowstwomegakaryocyteswithmultilobulatednucleiand
voluminouscytoplasm.Anormalneutrophil(arrow)nexttothemegakaryocyte
illustratesthelargesizeofthesecells.

CourtesyofDavidSRosenthal,MD.

Graphic55409Version2.0

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Effectofspleensizeonplateletpooling

Thisfigureshowsthetwohourrecoveryinthegeneralcirculationof
radioactivelylabeledplateletstransfusedtoasplenic(red),normal(green),and
splenomegalic(orange)patients.Thevastmajorityofthesplenomegalic
patientshadcongestivesplenomegalysecondarytocirrhosiswithportal
hypertension.

Adaptedfrom:AsterRH.Poolingofplateletsinthespleen:roleinthepathogenesis
of'hypersplenic'thrombocytopenia.JClinInvest196645:645.

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Causesofthrombocytopenia

Falselylowplateletcounts(pseudothrombocytopenia)
InvitroplateletclumpingcausedbyEDTAdependentagglutinins(naturallyoccurringantibodies)

Invitroplateletclumpingcausedbyaninsufficientlyanticoagulatedspecimen

InvitroplateletclumpingcausedbyglycoproteinIIb/IIIainhibitors(eg,abciximab)(NOTE:thesecan
alsocausetruethrombocytopenia)

Giantplateletscountedbyautomatedcounteraswhitebloodcellsratherthanplatelets

Commoncausesofthrombocytopenia
Primaryimmunethrombocytopenia(ITP)

Druginducedimmunethrombocytopenia(DITP)

Heparin(NOTE:specialcase,alsocancausethrombosis)

Quinine(asinoverthecountertabletsforlegcrampsalsoinbeverages)

Sulfonamides(eg,trimethoprimsulfamethoxazole[BactrimSeptra])

Acetaminophen(Tylenol,Panadol)

Cimetidine(Tagamet)

Ibuprofen(Advil,Motrin)

Naproxen(Aleve,Midol)

Ampicillin(Omnipen,ApoAmpi)

Piperacillin(Pipracil,Zosyn)

Vancomycin(Vancocin)

GlycoproteinIIb/IIIainhibitors(abciximab[ReoPro],tirofiban[Aggrastat],eptifibatide[Integrilin])

Foodandbeverages

Quininecontainingbeverages(tonicwater,Schweppesbitterlemon)

Infections

HIV

HepatitisC

EpsteinBarrvirus(EBVcanbeassociatedwithinfectiousmononucleosis)

H.pylori(suspectedinpatientswithsymptomsofdyspepsiaorpepticulcerdisease)

Sepsiswithdisseminatedintravascularcoagulation(DIC)

Intracellularparasites(eg,malaria,babesia)

Hypersplenismduetochronicliverdisease

Alcohol

Nutrientdeficiencies(eg,vitaminB12,folate,copper)

Rheumatologic/autoimmunedisorders(eg,systemiclupuserythematosus,rheumatoid
arthritis)

Pregnancy

Gestationalthrombocytopenia

Preeclampsia

HELLPsyndrome(hemolysis,elevatedliverfunctiontests,lowplatelets)

Othercausesofthrombocytopenia

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Myelodysplasia

Suspectedinolderpatients,inwhomabonemarrowbiopsymaybeappropriate

Cancerwithdisseminatedintravascularcoagulation

Cancerwithbonemarrowinfiltrationorsuppression(eg,lymphoma,leukemia,somesolid
tumors)

Paroxysmalnocturnalhemoglobinuria(PNH)

Thromboticmicroangiopathy(TMA)

Thromboticthrombocytopenicpurpura(TTP)ismanifestedbythrombocytopeniaandmicroangiopathic
hemolyticanemiafever,renalfailure,and/orneurologicsymptomsmayormaynotbepresent.

Hemolyticuremicsyndrome(HUS)istypicallyseeninchildrenfollowinginfectionwithaShigatoxin
producingorganism(E.coliorShigella).

DruginducedTMAmayoccurwithquinine,certaincancertherapies,calcineurininhibitors,andothers

Antiphospholipidsyndrome(APS)

Aplasticanemia

Inheritedthrombocytopenias

Animportantconsideration,especiallyinyoungpatientswhodonotrespondtotreatment.Some
specificsyndromesarelisted.However,manypatientsappeartohaveautosomaldominant
thrombocytopeniawithnootherclinicalfeatures.
VonWillebranddiseasetype2B
WiskottAldrichsyndrome
Alportsyndrome
MayHegglinanomaly
Fanconisyndrome
BernardSouliersyndrome
Thrombocytopeniaabsentradiussyndrome

Thetablelistspossiblecausesofisolatedthrombocytopenia.RefertotheUpToDatetopics
onthrombocytopenia,immunethrombocytopenia,heparininducedthrombocytopenia,anddruginduced
thrombocytopeniaforfurtherdetailsandamorecompletelistofdrugsthatcancausedruginduced
thrombocytopenia.

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Drugsassociatedwithisolatedthrombocytopenia

Drug Mechanism(s)

Abciximab DITP

Acetaminophen DITPantibodiesreactwithadrugmetabolite,nottheunmodified
drug

Alemtuzumab ITPlikesyndrome*

Amiodarone DITP

Betalactamantibiotics(eg, DITP
penicillins,cephalosporins)

Carbamazepine DITP

Ceftriaxone DITP

Daptomycin Bonemarrowsuppression(dosedependent)

Eptifibatide DITP

Ethambutol DITP

Furosemide DITP

Goldcompounds Bonemarrowsuppression

Haloperidol DITP

Heparin Drugdependentantibodiesthatalsoactivateplateletsandare
associatedwiththrombosis

Ibuprofen DITPinsomepatients,antibodiesreactwiththeunmodifieddrugin
others,antibodiesonlyreactwithadrugmetabolite

Irinotecan DITP

Levofloxacin DITP

Linezolid Bonemarrowsuppression(dosedependent)

Measlesmumpsrubella(MMR) ITPlikesyndrome*
vaccine

Mirtazapine DITP

Naproxen DITPantibodiesreactwithadrugmetabolite,nottheunmodified
drug

Oxaliplatin DITP

Penicillin DITP

Phenytoin DITP

Piperacillin DITP

Quinidine DITP

Quinine DITP

Ranitidine DITP

Rifampin DITP

Simvastatin DITP

Sulfonamides DITP

Suramin DITP

Tirofiban DITP

Trimethoprimsulfamethoxazole DITPantibodiesreactwiththesulfamethoxazoleantibodiesto
trimethoprimhavenotbeenidentified

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Valproicacid Bonemarrowsuppression(dosedependent)

Vancomycin DITP

Thistablelistsdrugswithevidenceforacausalassociationwithisolatedthrombocytopenia,fromclinical
datainpublishedcasereports,identificationofdrugdependent,plateletreactiveantibodies,orbothit
alsoliststheirmechanisms.Criteriaforevaluatingreportsofadruginducedetiologyinclude(1)Useof
thedrugprecededdevelopmentthrombocytopeniaandplateletcountrecoverywassustainedand
completefollowingdrugdiscontinuation(2)Nootherdrugswereusedpriortodevelopmentof
thrombocytopeniaorplateletcountremainednormaldespitecontinuationorreintroductionofotherdrugs
(3)Otheretiologiesforthrombocytopeniawereeliminated(4)Reexposuretothecandidatedrugcaused
recurrentthrombocytopeniaordrugdependentantiplateletantibodiesweredemonstrated.Drugsinbold
havebeenmostcommonlyimplicatedinacausalrelationship.Drugdependentantibodieshavebeenshown
forallagentsassociatedwithDITP.RefertoothercontentinUpToDateondruginducedthrombocytopenia
forfurtherinformation.

DITP:druginducedimmunethrombocytopenia(ie,thrombocytopeniacausedbydrugdependentantibodies)
ITP:immunethrombocytopenia,whichiscausedbyanautoimmunemechanismthatnolongerrequiresthe
presenceofthedrug.
*Arareadversereactiontoalemtuzumabresultsinprolonged,severethrombocytopeniathatresponds
toimmunosuppressivetherapy.
Quininecanalsocauseathromboticmicroangiopathyand/orothercytopenias.

AdaptedfromReeseJA,LiX,HaubenM,etal.Identifyingdrugsthatcauseacutethrombocytopenia:ananalysis
using3distinctmethods.Blood2010116:2127GeorgeJN,RaskobGE,ShahSR,etal.Druginduced
thrombocytopenia:asystematicreviewofpublishedcasereports.AnnInternMed1998129:886andArnold
DM,NaziI,WarkentinTE,etal.Approachtothediagnosisandmanagementofdruginducedimmune
thrombocytopenia.TransfusionMedReviews,201327:137.

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Commerciallyavailablesourcesofquinine

Availableformsofquinine:
Quininesulfatecapsules/tablets(asantimalarialtherapyorforlegcramps)

Quininecontainingbeverages(eg,quininewater,tonicwater,bitterlemon,ginandtonic)

Quinineisalsoaddedtootherpopularbeveragesbecauseofitsfluorescentproperties(eg,"jelloshots,"
"shocktails")

HerbalpreparationscontainingquinineorbarkfromtheCinchonatree*

IntheUnitedStates,quininetabletsareavailableonlybyprescriptionforthetreatmentofmalaria(as
Qualaquin).Inothercountries,quininemaybeavailableforlegcrampsbyprescriptionoroverthe
counter.Webelievealloftheproductslistedabovehavethepotentialforcausingdruginducedimmune
thrombocytopenia(DITP)and/orimmunemediateddruginducedthromboticmicroangiopathy(DITMA).

Adaptedfrom:LilesNW,PageEE,LilesAL,etal.Diversityandseverityofadversereactionstoquinine:a
systematicreview.AmJHematol201691:461.

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NCICTCAEv4.0hematologictoxicity

Blood
Grade1 Grade2 Grade3 Grade4 Grade5
element

Neutrophils <LLNto 1000to 500to <500/microL


1500/microL 1500/microL 1000/microL

Platelets <LLNto 50,000to 25,000to <25,000/microL


75,000/microL 75,000/microL 50,000/microL

Hemoglobin <LLNto10 8.0to10.0 <8.0g/dL Lifethreatening Death


g/dL g/dL consequences
urgent
intervention
indicated

Lymphocytes <LLNto 500to 200to <200/microL


(total) 800/microL 800/microL 500/microL

CD4count <LLNto 200to 50to <50/microL


500/microL 500/microL 200/microL

Febrile ANC Lifethreatening Death


neutropenia <1000/microL consequences
withasingle urgent
temperature intervention
>38.3C indicated
(100.4F)ora
sustained
temperature
38C(100F)
formorethan
onehour

Neutropenia,thrombocytopenia,anemia,andlymphocytopeniaaredeterminedfromthecompleteblood
count.Allpatientswithfeverinthesettingofchemotherapyinducedneutropeniarequireimmediate
medicalattentionregardlessofthetoxicitygrade.RefertoUpToDatetopicsonfebrileneutropenia
regardingthemanagementofthesepatients.

NCICTCAE:NationalCancerInstituteCommonTerminologyCriteriaforAdverseEventsLLN:lowerlimitof
normal.Cells/microLisequivalenttocells/mm 3orcellsx10 9/L.

Reproducedfrom:CommonTerminologyCriteriaforAdverseEvents(CTCAE),Version4.0,June2010,National
InstitutesofHealth,NationalCancerInstitute.Availableat:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_20100614_QuickReference_5x7.pdf(AccessedOctober22,
2013).

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SupplementationafterRouxenYgastricbypassandgastricsleeve
procedures

Representative
Supplement Dosage* Monitoring Comment
preparations

Multivitaminwithmineralsandiron,oneortwoperday,eachchewabletablet(orliquid
equivalent)minimallycontaining :

VitaminA 500mcg Multivitaminswith


(1600units) minerals(including
iron):
VitaminB1 1.2mg Thiamine Thiaminedeficiency
(thiamine) Representativetrade (optional) hasbeenassociated
names(US)include: withintractable
Erythrocyte
Centrum(NOT vomitingfollowing
transketolase
CentrumSilveras bariatricsurgeryand
activity
mineralcontentistoo Wernicke
(optional)
low),Centrum encephalopathyhas
Performance,OneA beenreported.See
DayMaximum,Equate text.
CompleteMultivitamin
VitaminE 10mg
forAdults
VitaminK Male:120 Prothrombin
mcgFemale Time/INR
90mcg (optionalasa
measureof
vitaminK
status)

Iron 10mg TIBC,ferritin,


elemental transferrin,CBC

Folicacid 400mcg RBCfolate


(optional)

Biotin 30mcg

Selenium 55mcg

Zinc Male:11mg Zincdeficiencymaybe


Female:8mg associatedwith
chronicdiarrhea

Copper 2mg Serumcopper

CalciumandvitaminD

Calciumcitrate 1200to1500 Elementalcalcium 25 Calciumcitrate


Calcium mg(elemental content: Hydroxyvitamin preparationsmaybe
carbonate(see calcium)per Tablets,capsules:180, D betterabsorbedthan
comment) daypreferably 200,250mg IntactPTH calciumcarbonate
intwoequally (optional) underconditionsof
Effervescenttablet:500
divideddoses reducedgastricacidity
mg
butrequire
Oralsuspension:760 consumptionofmore
mgper5mL tablets.Donottake
withintwohoursof
ironsupplement.

VitaminD3 800unitsper Tablets,capsules:400,


(cholecalciferol) day 1000,2000units
Chewabletablet:400
units
Oraldrops:400units

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perdrop

Ironandascorbicacid

Ferrous 40to65mg Combination(eg, Ironstudies, Ironsupplementation


fumarate (elemental VitronC)ferrous ferritin,CBC isbasedon
Ferrous iron)perday fumarate(65mg monitoring.Ironis
gluconate for elemental)withascorbic containedinthe
premenopausal acid(125mg)ferrous multivitaminmineral
Ferroussulfate
women sulfateoralliquid:44or tabletandadditional
18to27mg 60mgelementalper5 supplementationisnot
(elemental mLascorbicacidliquid: recommendedunless
iron)perday 100mg/mL thepatienthas
forothers documentediron
deficiency.If
Maybe
additional
includedin
supplementation
multivitamin
indicated,100to150
mgascorbicacid
enhancesiron
absorptionunder
conditionsofreduced
gastricacidity.Donot
takewithintwohours
ofcalciumsupplement.

VitaminB12(cyanocobalamin)

Oraltablet 500to1000 Tablet:250,500,1000 CBC,Vitamin B12deficiencyisa


mcgperday mcg B12 frequentcomplication
(methylmalonic withinoneyearof
Sublingualor 500to1000 Sublingualtabletor
acid, RYGBsurgeryin
buccaltablet mcgperday lozenge500mcg
homocysteine absenceofadequate
Sublingual 400mcgper 200mcgperspray optional) supplementation
spray day

Intranasalspray 500mcgonce 500mcgper0.1mL


perweek intranasalspray

Intramuscular 1000mcgIM 1000mcgpermL


injection onceper injection
monthor3000
mcgIMonce
everysix
months

Patientswithdeficiencystateswillneedtreatmentbeyondtheserecommendations.

IM:intramuscularlyTIBC:totalironbindingcapacityRYGB:RouxenYgastricbypassPTH:parathyroid
hormoneCBC:completebloodcountRBC:redbloodcell.
*Maintenancedosageforadult,oraladministration,unlessspecifiedotherwise.
Routinelabmonitoringatbaselineandeverythreetosixmonthsduringfirstyear,thenannuallythereafter.
Seetextforadditionalinformation.
MultivitaminshouldprovideUSFoodandDrugAdministrationdailyrecommendedintakeforothervitaminsand
minerals.Ironcontainingmultivitaminpreparationsthatdonotcontaincalciummaybepreferred.Calcium
shouldbeadministeredasaseparatepreparationatleasttwohoursbeforeoraftermultivitaminwithiron
supplementstoincreaseabsorption.

Adaptedfrom:
1.MechanickJI,KushnerRF,SugermanHJ,etal.AmericanAssociationofClinicalEndocrinologists,The
ObesitySociety,andAmericanSocietyforMetabolic&BariatricSurgeryMedicalguidelinesforclinical
practicefortheperioperativenutritional,metabolic,andnonsurgicalsupportofthebariatricsurgery
patient.EndocrPract200814Suppl1:1.
2.SnyderMarlowG,etal.NutritionCareforpatientsundergoinglaparoscopicsleevegastrectomyforweight
loss.JAmDietAssoc2010110:600.

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Graphic79014Version5.0

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Commonpresentationsofpatientswiththrombocytopenia

Officepresentation
Asymptomatic,ISOLATED,incidentallydiscoveredthrombocytopenia

Common

Immunethrombocytopenia(ITP)

Gestationalthrombocytopeniaduringpregnancy

Lesscommon

Occultliverdisease

Myelodysplasticsyndrome

Congenitalthrombocytopenia

HIVinfection

Symptomatic,severethrombocytopenia

Common

Druginducedthrombocytopenia

Immunethrombocytopenia(ITP)

Hospitalpresentation
Thrombocytopeniaaspartofamultisystemillness

Common

Druginducedthrombocytopenia

Heparininducedthrombocytopenia

Liverdisease

Sepsiswithdisseminatedintravascularcoagulation(DIC)

CancerwithDIC

Pregnancy
Preeclampsia
HELLPsyndrome(hemolysis,elevatedliverenzymes,andlowplatelets)
AbruptioplacentaewithDIC

Multiorganfailuresyndromes

Lesscommon

Thromboticthrombocytopenicpurpura(TTP,acquiredorhereditary)

Druginducedthromboticmicroangiopathy(DITMA)

Hemolyticuremicsyndrome(HUS)

Lymphoma

Acuteleukemia

Antiphospholipidsyndrome

Paroxysmalnocturnalhemoglobinuria(PNH)

Nutrientdeficiency(vitaminB12,folate,copper)

RefertoUpToDatetopicsonthrombocytopeniaforfurtherdetails.

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Clinicalmanifestationsofbleedingdisorders

Bleedingdisorder

Bleeding Clottingfactor
symptoms deficiencies(eg,factor
Plateletdefects(qualitativeorquantitative)
VIIIorfactorIX
deficiencies)

Overviewof Mucocutaneousbleeding Deeptissuebleeding


bleeding (oralcavity,nasal,gastrointestinal,and (includingjointsand
events genitourinarysites) muscles)

Excessive Yes Notusually


bleedingafter
minorcuts

Petechiae Common Uncommon

Ecchymoses Generallysmallandsuperficialmaybesignificant, Maydeveloplarge


dependinguponthedefectordegreeof subcutaneousandsofttissue
thrombocytopenia hematomas

Hemarthroses, Uncommon Commoninseveredeficiency


muscle statesorinassociationwith
hematomas injuryinthosewithmildto
moderatedeficiencystates

Bleedingwith Oftenimmediate,withdegreeofbleedingdependent Maybeassociatedeitherwith


invasive upontheseverityofthedefect,rangingfromnone(eg, proceduralbleedingor
procedures, milddegreesofthrombocytopeniaormildplatelet delayedbleeding,depending
including functiondefect)tomildtosevere(eg,Glanzmann uponthetypeandseverityof
surgery thrombasthenia) thedefect

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PetechiaeinImmuneThrombocytopenia(ITP)

Petechiaeinamanwithimmunethrombocytopenia(ITP).
(A)Dense,cutaneouspetechiaeonthefootandankle.Therearenopetechiaeon
thesoleofhisfoot,asiteatwhichthevesselsareprotectedbythestrong
subcutaneoustissue.
(B)Occasionalpetechiaeonthepatient'sfaceandlarge,bulloushemorrhageson
thebuccalmucosa,whicharerelatedtothelackofvesselprotectionbythe
submucosaltissue.Similarpetechiaeandhemorrhagicbullaecanbeseenin
patientswiththrombocytopeniaofanycause.

Reproducedwithpermissionfrom:SteinJH,InternalMedicine,5thed,Mosby,St.
Louis,1998.

Graphic71480Version7.0

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Immunethrombocytopenia(ITP)

Petechiaearepresentonthelegsofthispatientwithimmunethrombocytopenia
(ITP).

Reproducedwithpermissionfrom:www.visualdx.com.CopyrightLogicalImages,Inc.

Graphic76671Version4.0

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SkinlesionsinHenochSchnleinpurpura(IgA
vasculitis)

Clustersofpalpable,pruriticlesionsonthethighofapatientwithHenoch
Schnleinpurpura(IgAvasculitis).Theselesionscouldbemistakenfor
thrombocytopenicpetechiae.

IgA:immunoglobulinA.

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Giantplateletsinhereditarymacrothrombocytopenia

Peripheralbloodsmearshowsmanygiantplatelets(arrows)inayoungwomanwith
congenitalthrombocytopenia.Thepatienthaspersistentseverethrombocytopeniaand
highfrequencysensorineuralhearingloss,aconstellationoffindingsconsistentwithone
ofthecongenitalmacrothrombocytopenias.Thepatienthadbeenerroneouslydiagnosed
ashavingimmunethrombocytopenia(ITP)duringchildhoodandhadbeentreated
withglucocorticoidsandsplenectomywithnoresponse.

1000X

CourtesyofGermanAPihan,MD,BethIsraelDeaconessMedicalCenter,Departmentof
Pathology,andJeffreyZwicker,MD,BethIsraelDeaconessMedicalCenter,Departmentof
Medicine.

Graphic72433Version8.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred

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cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic59683Version4.0

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Pseudothrombocytopeniaduetoplateletclumpingin
EDTA

Thisperipheralbloodsmearshowsplateletclumping(arrows)inanEDTA
anticoagulatedbloodsample.ThispatienthadanEDTAdependentplatelet
agglutininwhichcausedinvitroplateletclumping,resultinginanartifactuallylow
plateletcount(ie,"pseudothrombocytopenia").Noplateletclumpingwasseen,
andtheplateletcountwasnormal,inabloodsamplefromthispatient
anticoagulatedwithsodiumcitrate.

ReproducedwithpermissionfromBeutler,E,Lichtman,MA,Coller,BS,etal,
Hematology,5thed,McGrawHill,NewYork,1995.

Graphic68949Version2.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic59683Version4.0
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Peripheralsmearinmicroangiopathichemolyticanemia
showingpresenceofschistocytes

Peripheralbloodsmearfromapatientwithamicroangiopathichemolyticanemia
withmarkedredcellfragmentation.Thesmearshowsmultiplehelmetcells
(arrows)andotherfragmentedredcells(smallarrowhead)microspherocytes
arealsoseen(largearrowheads).Theplateletnumberisreducedthelarge
plateletinthecenter(dashedarrow)suggeststhatthethrombocytopeniaisdue
toenhanceddestruction.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic70851Version8.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic59683Version4.0

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Peripheralsmearinsevereautoimmunehemolytic
anemia

PeripheralbloodsmearfromapatientwithCoombspositiveautoimmune
hemolyticanemia.Thesmearshowsthepresenceofmanyspherocytes(red
arrows),onenucleatedredbloodcell(bluearrow),andanumberoflarger
polychromatophilicredcells(blackarrows),representingareticulocytosisin
responsetotheanemia.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic50601Version3.0

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HowellJollybodiesfollowingsplenectomy

Thisperipheralbloodsmearshowstworedbloodcells(RBCs)thatcontain
HowellJollybodies(blackarrows).HowellJollybodiesareremnantsofRBC
nucleithatarenormallyremovedbythespleen.Thus,theyareseeninpatients
whohaveundergonesplenectomy(asinthiscase)orwhohavefunctional
asplenia(eg,fromsicklecelldisease).Targetcells(bluearrows)areanother
consequenceofsplenectomy.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic60588Version6.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

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Spherocytes

Peripheralbloodsmearshowsmultiplespherocytes,whicharesmall,dark,dense
hyperchromicredcellswithoutcentralpallor(arrows).Thesefindingsare
compatiblewithhereditaryspherocytosisorautoimmunehemolyticanemia.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic70611Version4.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

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Peripheralbloodsmearinautoimmunehemolytic
anemia(AIHA)

ThisperipheralbloodsmearfromapatientwithAIHAduetoawarmreactive
immunoglobulinG(IgG)antibodydemonstratesthepresenceofmanydarkred,
smallmicrospherocytes(redarrows)andlargerspherocytes(blackarrow)
(x1000).Manylarge,irregular,bluetintedredcellsarealsopresent,
representingreticulocytes(bluearrows).

Reproducedfrom:WareRE.Autoimmunehemolyticanemia.In:NathanandOski's
HematologyofInfancyandChildhood,7thEd,OrkinS,NathanDG,GinsburgD,etal
(Eds),Saunders,Philadelphia2009.IllustrationusedwiththepermissionofElsevier
Inc.

Graphic53523Version4.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

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Leukoerythroblasticperipheralbloodsmear

Leukoerythroblasticperipheralbloodsmearshowingthepresenceofnucleated
redcellsandimmaturewhitecells.Thispatternoccurswithmarrow
replacement,usuallyduetofibrosisthatmaybeidiopathic(eg,primary
myelofibrosis)orreactivetoconditionssuchasmetastaticcancer.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic68110Version3.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

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Teardropshapedredbloodcells(dacrocytes)

Thisperipheralsmearfromapatientwithbonemarrowfibrosisshowsnumerous
teardropshapedredcells(arrows).Notethattheteardropsarepointedin
severaldifferentdirections,rulingoutanartifactduetopreparationofthe
smear.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic55274Version4.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

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ToxicgranulationsandDhlebodiesin
infection/inflammation

Leftpanel:Peripheralbloodsmearshowsneutrophilswithtoxicgranulations,whichare
darkcoarsegranules.ADhlebodyisalsoseen(arrow).Rightpanel:Aneutrophilwith
toxicgranulations,vacuoles(anothertoxicchange),andaDhlebody(arrow).These
abnormalitiesarecharacteristicoftoxicsystemicillnesses.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic70248Version3.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

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Graphic59683Version4.0

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MyeloblastswithAuerrodinacutemyeloidleukemia

Peripheralsmearfromapatientwithacutemyeloidleukemia.Therearetwo
myeloblasts,whicharelargecellswithhighnucleartocytoplasmicratioand
nucleoli.Eachmyeloblasthasapink/redrodlikestructure(Auerrod)inthe
cytoplasm(arrows).

FromBrunningRD,McKennaRW.Tumorsofthebonemarrow.Atlasoftumor
pathology(electronicfascicle),Thirdseries,fascicle9,1994,Washington,DC.
ArmedForcesInstituteofPathology.

Graphic78291Version3.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic59683Version4.0

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Decreasednuclearlobesinmyelodysplasia(pseudo
PelgerHuetanomaly)

Peripheralbloodsmearfromapatientwithrefractoryanemiawithexcessblasts
(RAEB)showsaneutrophilwithabilobedpseudoPelgerHuet(Pelgeroid)
nucleus.Thetwolobesareconnectedbyathinstrand(arrow)givinga"pince
nez"appearance.Thesenucleilookidenticaltothethoseseenintheinherited
PelgerHuetanomaly.Thisneutrophilalsohasmarkedlyreducedgranulation,a
findingcommonlyseeninthemyelodysplasticsyndromes.

FromBrunning,RD,McKenna,RW.Tumorsofthebonemarrow.Atlasoftumor
pathology(electronicfascicle),Thirdseries,fascicle9,1994,Washington,DC.
ArmedForcesInstituteofPathology.

Graphic71990Version3.0

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Megaloblasticbloodpicture

Peripheralbloodsmearshowingahypersegmentedneutrophil(sevenlobes)and
macroovalocytes,apatternthatcanbeseenwithcobalaminorfolate
deficiency.

CourtesyofStanleyLSchrier,MD.

Graphic58820Version3.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic59683Version4.0

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Bonemarrowbiopsyinaplasticanemia

Bonemarrowbiopsyinaplasticanemia.Therearevirtuallynohematopoietic
cells,andthemarrowspaceconsistsoffatandstroma.

CourtesyofStanleyLSchrier,MD.

Graphic63867Version2.0

Normalbonemarrowbiopsyatlowpower

Lowpowerviewofanormalbonemarrowbiopsy.Theoverallcellularityis
between30and70percent,withtheremainderofthespacebeingoccupied
byfatandstroma.

CourtesyofStanleyLSchrier,MD.

Graphic68384Version2.0

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Bonemarrowaspirateinaplasticanemia

Lowpower(10X)viewofabonemarrowaspirateinapatientwithaplastic
anemia.Thesupportingstromalmeshworkofthebonemarrowspiculeis
outlinedbytheredarrows.However,hematopoieticcellsaresparse,givingthe
patternofanemptywickerbasket.

CourtesyofCarolavonKapff,SH(ASCP).

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Megaloblasticerythropoiesis

Comparisonofnormalandmegaloblasticerythropoiesiswithrespecttoerythroid
precursorsinthebonemarrow.Leftpanel:Normalerythropoiesis.Rightpanel:
Megaloblasticerythropoiesis.

CourtesyofStanleyLSchrier,MD.

Graphic68005Version1.0

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Myelodysplasticsyndromewithabnormal
megakaryocyticmaturation

Bonemarrowaspiratefromapatientwithmyelodysplasticsyndrome.The
megakaryocytesareabnormal,withmultiplesmalllobesseeminglydisconnected
fromeachother("Pawnball"changes,arrows).(WrightGiemsa).

CourtesyofDavidSRosenthal,MD.

Graphic59897Version1.0

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Ringsideroblastsinrefractoryanemiawithring
sideroblasts(RARS)

Prussianbluestainofthebonemarrowinapatientwithrefractoryanemiaand
ringsideroblasts(RARS).Bluestainedferritinirondepositsinthemitochondria
oferythroidprecursorsformanapparentringaroundthenucleus(seearrows).

CourtesyofStanleyLSchrier,MD.

Graphic65887Version5.0

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Myelofibrosisbonemarrowbiopsy

Bonemarrowbiopsyinmyelofibrosisshowsreplacementofthemarrowwith
fibroustissue.

CourtesyofStanleyLSchrier,MD.

Graphic57384Version2.0

Normalbonemarrowbiopsyatlowpower

Lowpowerviewofanormalbonemarrowbiopsy.Theoverallcellularityis
between30and70percent,withtheremainderofthespacebeingoccupied
byfatandstroma.

CourtesyofStanleyLSchrier,MD.

Graphic68384Version2.0

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Bonemarrowbiopsyinprimarymyelofibrosisstainedfor
collagen

Bonemarrowbiopsyfromapatientwithprimarymyelofibrosisstainedfor
collagen(trichromestain).Themarrowcavity(arrows)istraversedbyblue
stainingcollagenbands.

CourtesyofStephenALandaw,MD.

Graphic69139Version2.0

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Clumpoftumorcellsinthebonemarrow

Bonemarrowaspiratefromapatientwithcarcinomametastatictothebone
marrow,illustratingthepresenceofalargeclumpoftumorcells(arrow),
surroundedbynormalmarrowelements.Notethatthecellularoutlineswithin
theclumpoftumorcellsareindistinct.Thisisnotacharacteristicofanygroup
ofcellsnormallyseeninthebonemarrow.

CourtesyofDavidSRosenthal,MDandAnnaJMitus,MD.

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ContributorDisclosures
JamesNGeorge,MD Grant/Research/ClinicalTrialSupport:Ablynx[TTP(caplacizumab)]. Donald
MArnold,MD,MSc Grant/Research/ClinicalTrialSupport:Novartis[ITP(eltrombopag)]Amgen[ITP
(romiplostim)]BristolMeyersSquibb[ITP(investigationalnewdrug)]Rigel[ITP(fostamatinib)].
Consultant/AdvisoryBoards:Amgen[ITP(romiplostim)]Novartis[ITP(eltrombopag)]Rigel[ITP
(fostamatinib)]Grifols[ITP(intravenousimmuneglobulin)UCB[ITP(investigationalnewdrug)]Rigel
[ITP(fostamatinib)]. LawrenceLKLeung,MD Nothingtodisclose JenniferSTirnauer,MD Nothing
todisclose

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,these
areaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsfor
referencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofall
authorsandmustconformtoUpToDatestandardsofevidence.

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