Approach To The Adult With Unexplained Thrombocytopenia - UpToDate

3/4/2017 ApproachtotheadultwithunexplainedthrombocytopeniaUpToDate
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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.
https://www.uptodate.com/contents/approachtotheadultwithunexplainedthrombocytopenia/print?source=search_result&search=thrombocytopenia&se 1/65
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
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
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.
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".)
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
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
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
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
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
https://www.uptodate.com/contents/approachtotheadultwithunexplainedthrombocytopenia/print?source=search_result&search=thrombocytopenia&s 10/65
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
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:
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.)
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
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
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
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.
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",
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
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.)
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.
REFERENCES
1.WilliamsonDR,AlbertM,HeelsAnsdellD,etal.Thrombocytopeniaincriticallyillpatients
receivingthromboprophylaxis:frequency,riskfactors,andoutcomes.Chest2013144:1207.
2.BuckleyMF,JamesJW,BrownDE,etal.Anovelapproachtotheassessmentofvariationsinthe
humanplateletcount.ThrombHaemost200083:480.
3.SegalJB,MoliternoAR.Plateletcountsdifferbysex,ethnicity,andageintheUnitedStates.Ann
Epidemiol200616:123.
4.vanBladelER,LaarhovenAG,vanderHeijdenLB,etal.Functionalplateletdefectsinchildren
withseverechronicITPastestedwith2novelassaysapplicableforlowplateletcounts.Blood
2014123:1556.
5.WesselsP,HeynsAD,PietersH,etal.Animprovedmethodforthequantificationoftheinvivo
kineticsofarepresentativepopulationof111Inlabelledhumanplatelets.EurJNuclMed1985
10:522.
6.HarkerLA,FinchCA.Thrombokineticsinman.JClinInvest196948:963.
7.MasonKD,CarpinelliMR,FletcherJI,etal.Programmedanuclearcelldeathdelimitsplateletlife
span.Cell2007128:1173.
8.DowlingMR,JosefssonEC,HenleyKJ,etal.Plateletsenescenceisregulatedbyaninternal
timer,notdamageinflictedbyhits.Blood2010116:1776.
9.LeslieSD,ToyPT.Laboratoryhemostaticabnormalitiesinmassivelytransfusedpatientsgiven
redbloodcellsandcrystalloid.AmJClinPathol199196:770.
10.CountsRB,HaischC,SimonTL,etal.Hemostasisinmassivelytransfusedtraumapatients.Ann
Surg1979190:91.
11.AsterRH.Poolingofplateletsinthespleen:roleinthepathogenesisof"hypersplenic"
thrombocytopenia.JClinInvest196645:645.
12.SheikhMY,RaoufiR,AtlaPR,etal.Prevalenceofcirrhosisinpatientswiththrombocytopenia
whoreceivebonemarrowbiopsy.SaudiJGastroenterol201218:257.
13.MendesFD,SuzukiA,SandersonSO,etal.Prevalenceandindicatorsofportalhypertensionin
patientswithnonalcoholicfattyliverdisease.ClinGastroenterolHepatol201210:1028.
14.WatsonJC,HadlerSC,DykewiczCA,etal.Measles,mumps,andrubellavaccineuseand
strategiesforeliminationofmeasles,rubella,andcongenitalrubellasyndromeandcontrolof
mumps:recommendationsoftheAdvisoryCommitteeonImmunizationPractices(ACIP).MMWR
RecommRep199847:1.
15.MantadakisE,FarmakiE,BuchananGR.Thrombocytopenicpurpuraaftermeaslesmumps
rubellavaccination:asystematicreviewoftheliteratureandguidanceformanagement.JPediatr
2010156:623.
16.KarimiO,GoorhuisA,SchinkelJ,etal.Thrombocytopeniaandsubcutaneousbleedingsina
patientwithZikavirusinfection.Lancet2016387:939.
17.ZammarchiL,StellaG,MantellaA,etal.ZikavirusinfectionsimportedtoItaly:clinical,
immunologicalandvirologicalfindings,andpublichealthimplications.JClinVirol201563:32.
18.NeunertC,LimW,CrowtherM,etal.TheAmericanSocietyofHematology2011evidencebased
practiceguidelineforimmunethrombocytopenia.Blood2011117:4190.
19.GeorgeJN,VeselySK,WoolfSH.Conflictsofinterestandclinicalrecommendations:comparison
oftwoconcurrentclinicalpracticeguidelinesforprimaryimmunethrombocytopeniadevelopedby
differentmethods.AmJMedQual201429:53.
20.RousanTA,AldossIT,CowleyBDJr,etal.Recurrentacutethrombocytopeniainthehospitalized
patient:sepsis,DIC,HIT,orantibioticinducedthrombocytopenia.AmJHematol201085:71.
21.AzunoY,YagaK,SasayamaT,KimotoK.ThrombocytopeniainducedbyJui,atraditional
Chineseherbalmedicine.Lancet1999354:304.
22.OhmoriT,NishiiK,HagiharaA,etal.Acutethrombocytopeniainducedbyjui,atraditionalherbal
medicine.JThrombHaemost20042:1479.
23.ArnoldJ,OuwehandWH,SmithGA,CohenH.Ayoungwomanwithpetechiae.Lancet1998
352:618.
24.AchterberghR,VermeerHJ,CurtisBR,etal.Thrombocytopeniainanutshell.Lancet2012
379:776.
25.SwisherKK,DoanJT,VeselySK,etal.Pancreatitisprecedingacuteepisodesofthrombotic
thrombocytopenicpurpurahemolyticuremicsyndrome:reportoffivepatientswithasystematic
reviewofpublishedreports.Haematologica200792:936.
26.FishmanAD,HoffmanA,VolterraF,etal.Intracavalandintracardiacmetastatic
nonseminomatousgermcelltumor:ararecauseofhemolyticanemiaandthrombocytopenia.
CancerInvest200220:996.
27.StasiR,AmadoriS,OsbornJ,etal.Longtermoutcomeofotherwisehealthyindividualswith
incidentallydiscoveredborderlinethrombocytopenia.PLoSMed20063:e24.
28.HuiP,CookDJ,LimW,etal.Thefrequencyandclinicalsignificanceofthrombocytopenia
complicatingcriticalillness:asystematicreview.Chest2011139:271.
29.StraussR,WehlerM,MehlerK,etal.Thrombocytopeniainpatientsinthemedicalintensivecare
unit:bleedingprevalence,transfusionrequirements,andoutcome.CritCareMed200230:1765.
30.VanderschuerenS,DeWeerdtA,MalbrainM,etal.Thrombocytopeniaandprognosisin
intensivecare.CritCareMed200028:1871.
31.ArnoldDM,LimW.Arationalapproachtothediagnosisandmanagementofthrombocytopenia
inthehospitalizedpatient.SeminHematol201148:251.
32.GreinacherA,SellengS.HowIevaluateandtreatthrombocytopeniaintheintensivecareunit
patient.Blood2016128:3032.
33.ReeseJA,LiX,HaubenM,etal.Identifyingdrugsthatcauseacutethrombocytopenia:an
analysisusing3distinctmethods.Blood2010116:2127.
34.WarkentinTE.Heparininducedthrombocytopeniaincriticallyillpatients.CritCareClin2011
27:805.
35.O'DonnellE,ShepherdC,NeffA.Immunethrombocytopeniafromvancomycininorthopedic
cement.AmJHematol200782:1122.
36.LadhaniS,KhatriP,ElBashirH,ShingadiaD.Importedmalariaisamajorcauseof
thrombocytopeniainchildrenpresentingtotheemergencydepartmentineastLondon.BrJ
Haematol2005129:707.
37.PatelU,GandhiG,FriedmanS,NiranjanS.Thrombocytopeniainmalaria.JNatlMedAssoc
200496:1212.
38.WestKA,AndersonDR,McAlisterVC,etal.Alloimmunethrombocytopeniaafterorgan
transplantation.NEnglJMed1999341:1504.
39.SavageRA.PseudoleukocytosisduetoEDTAinducedplateletclumping.AmJClinPathol1984
81:317.
40.PayneBA,PierreRV.Pseudothrombocytopenia:alaboratoryartifactwithpotentiallyserious
consequences.MayoClinProc198459:123.
41.PegelsJG,BruynesEC,EngelfrietCP,vondemBorneAE.Pseudothrombocytopenia:an
immunologicstudyonplateletantibodiesdependentonethylenediaminetetraacetate.Blood
198259:157.
42.GarciaSuarezJ,CaleroMA,RicardMP,etal.EDTAdependentpseudothrombocytopeniain
ambulatorypatients:clinicalcharacteristicsandroleofnewautomatedcellcountinginits
detection.AmJHematol199239:146.
43.VicariA,BanfiG,BoniniPA.EDTAdependentpseudothrombocytopaenia:a12month
epidemiologicalstudy.ScandJClinLabInvest198848:537.
44.BartelsPC,SchoorlM,LombartsAJ.ScreeningforEDTAdependentdeviationsinplatelet
countsandabnormalitiesinplateletdistributionhistogramsinpseudothrombocytopenia.ScandJ
ClinLabInvest199757:629.
45.FiorinF,SteffanA,PradellaP,etal.IgGplateletantibodiesinEDTAdependent
pseudothrombocytopeniabindtoplateletmembraneglycoproteinIIb.AmJClinPathol1998
110:178.
46.CescaC,BenEzraJ,RileyRS.Plateletsatellitismaspresentingfindinginmantlecelllymphoma.
Acasereport.AmJClinPathol2001115:567.
47.MontagueN,BlackwelderP,AlsayeghH,etal.Plateletsatellitismanddualsurface
immunoglobulinlightchainexpressionincirculatingsplenicmarginalzonelymphomacells.Ann
DiagnPathol201317:117.
48.BobbaRK,DollDC.Plateletsatellitismasacauseofspuriousthrombocytopenia.Blood2012
119:4100.
49.BizzaroN,GoldschmedingR,vondemBorneAE.PlateletsatellitismisFcgammaRIII(CD16)
receptormediated.AmJClinPathol1995103:740.
50.PoddaGM,PuglianoM,FemiaEA,etal.TheplateletcountinEDTAanticoagulatedbloodfrom
patientswiththrombocytopeniamaybeunderestimatedwhenmeasuredinroutinelaboratories.
AmJHematol201287:727.
Topic6680Version41.0
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
Bonemarrowmegakaryocytes
Bonemarrowaspirateshowstwomegakaryocyteswithmultilobulatednucleiand
voluminouscytoplasm.Anormalneutrophil(arrow)nexttothemegakaryocyte
illustratesthelargesizeofthesecells.
CourtesyofDavidSRosenthal,MD.
Effectofspleensizeonplateletpooling
Thisfigureshowsthetwohourrecoveryinthegeneralcirculationof
radioactivelylabeledplateletstransfusedtoasplenic(red),normal(green),and
splenomegalic(orange)patients.Thevastmajorityofthesplenomegalic
patientshadcongestivesplenomegalysecondarytocirrhosiswithportal
hypertension.
Adaptedfrom:AsterRH.Poolingofplateletsinthespleen:roleinthepathogenesis
of'hypersplenic'thrombocytopenia.JClinInvest196645:645.
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)
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
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.
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
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.
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.
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).
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
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.
Commonpresentationsofpatientswiththrombocytopenia
Officepresentation
Asymptomatic,ISOLATED,incidentallydiscoveredthrombocytopenia
Common
Immunethrombocytopenia(ITP)
Gestationalthrombocytopeniaduringpregnancy
Lesscommon
Occultliverdisease
Myelodysplasticsyndrome
Congenitalthrombocytopenia
HIVinfection
Symptomatic,severethrombocytopenia
Common
Druginducedthrombocytopenia
Hospitalpresentation
Thrombocytopeniaaspartofamultisystemillness
Common
Druginducedthrombocytopenia
Heparininducedthrombocytopenia
Liverdisease
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.
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
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.
Petechiaearepresentonthelegsofthispatientwithimmunethrombocytopenia
(ITP).
Reproducedwithpermissionfrom:www.visualdx.com.CopyrightLogicalImages,Inc.
SkinlesionsinHenochSchnleinpurpura(IgA
vasculitis)
Clustersofpalpable,pruriticlesionsonthethighofapatientwithHenoch
Schnleinpurpura(IgAvasculitis).Theselesionscouldbemistakenfor
thrombocytopenicpetechiae.
IgA:immunoglobulinA.
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.
Normalperipheralbloodsmear
Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.
CourtesyofCarolavonKapff,SH(ASCP).
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.
Peripheralsmearinmicroangiopathichemolyticanemia
showingpresenceofschistocytes
Peripheralbloodsmearfromapatientwithamicroangiopathichemolyticanemia
withmarkedredcellfragmentation.Thesmearshowsmultiplehelmetcells
(arrows)andotherfragmentedredcells(smallarrowhead)microspherocytes
arealsoseen(largearrowheads).Theplateletnumberisreducedthelarge
plateletinthecenter(dashedarrow)suggeststhatthethrombocytopeniaisdue
toenhanceddestruction.
Peripheralsmearinsevereautoimmunehemolytic
anemia
PeripheralbloodsmearfromapatientwithCoombspositiveautoimmune
hemolyticanemia.Thesmearshowsthepresenceofmanyspherocytes(red
arrows),onenucleatedredbloodcell(bluearrow),andanumberoflarger
polychromatophilicredcells(blackarrows),representingareticulocytosisin
responsetotheanemia.
HowellJollybodiesfollowingsplenectomy
Thisperipheralbloodsmearshowstworedbloodcells(RBCs)thatcontain
HowellJollybodies(blackarrows).HowellJollybodiesareremnantsofRBC
nucleithatarenormallyremovedbythespleen.Thus,theyareseeninpatients
whohaveundergonesplenectomy(asinthiscase)orwhohavefunctional
asplenia(eg,fromsicklecelldisease).Targetcells(bluearrows)areanother
consequenceofsplenectomy.
Spherocytes
Peripheralbloodsmearshowsmultiplespherocytes,whicharesmall,dark,dense
hyperchromicredcellswithoutcentralpallor(arrows).Thesefindingsare
compatiblewithhereditaryspherocytosisorautoimmunehemolyticanemia.
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.
Leukoerythroblasticperipheralbloodsmear
Leukoerythroblasticperipheralbloodsmearshowingthepresenceofnucleated
redcellsandimmaturewhitecells.Thispatternoccurswithmarrow
replacement,usuallyduetofibrosisthatmaybeidiopathic(eg,primary
myelofibrosis)orreactivetoconditionssuchasmetastaticcancer.
Teardropshapedredbloodcells(dacrocytes)
Thisperipheralsmearfromapatientwithbonemarrowfibrosisshowsnumerous
teardropshapedredcells(arrows).Notethattheteardropsarepointedin
severaldifferentdirections,rulingoutanartifactduetopreparationofthe
smear.
ToxicgranulationsandDhlebodiesin
infection/inflammation
Leftpanel:Peripheralbloodsmearshowsneutrophilswithtoxicgranulations,whichare
darkcoarsegranules.ADhlebodyisalsoseen(arrow).Rightpanel:Aneutrophilwith
toxicgranulations,vacuoles(anothertoxicchange),andaDhlebody(arrow).These
abnormalitiesarecharacteristicoftoxicsystemicillnesses.
MyeloblastswithAuerrodinacutemyeloidleukemia
Peripheralsmearfromapatientwithacutemyeloidleukemia.Therearetwo
myeloblasts,whicharelargecellswithhighnucleartocytoplasmicratioand
nucleoli.Eachmyeloblasthasapink/redrodlikestructure(Auerrod)inthe
cytoplasm(arrows).
FromBrunningRD,McKennaRW.Tumorsofthebonemarrow.Atlasoftumor
pathology(electronicfascicle),Thirdseries,fascicle9,1994,Washington,DC.
ArmedForcesInstituteofPathology.
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.
Megaloblasticbloodpicture
Peripheralbloodsmearshowingahypersegmentedneutrophil(sevenlobes)and
macroovalocytes,apatternthatcanbeseenwithcobalaminorfolate
deficiency.
CourtesyofStanleyLSchrier,MD.
Bonemarrowbiopsyinaplasticanemia
Bonemarrowbiopsyinaplasticanemia.Therearevirtuallynohematopoietic
cells,andthemarrowspaceconsistsoffatandstroma.
Normalbonemarrowbiopsyatlowpower
Lowpowerviewofanormalbonemarrowbiopsy.Theoverallcellularityis
between30and70percent,withtheremainderofthespacebeingoccupied
byfatandstroma.
Bonemarrowaspirateinaplasticanemia
Lowpower(10X)viewofabonemarrowaspirateinapatientwithaplastic
anemia.Thesupportingstromalmeshworkofthebonemarrowspiculeis
outlinedbytheredarrows.However,hematopoieticcellsaresparse,givingthe
patternofanemptywickerbasket.
Megaloblasticerythropoiesis
Comparisonofnormalandmegaloblasticerythropoiesiswithrespecttoerythroid
precursorsinthebonemarrow.Leftpanel:Normalerythropoiesis.Rightpanel:
Megaloblasticerythropoiesis.
Myelodysplasticsyndromewithabnormal
megakaryocyticmaturation
Bonemarrowaspiratefromapatientwithmyelodysplasticsyndrome.The
megakaryocytesareabnormal,withmultiplesmalllobesseeminglydisconnected
fromeachother("Pawnball"changes,arrows).(WrightGiemsa).
CourtesyofDavidSRosenthal,MD.
Ringsideroblastsinrefractoryanemiawithring
sideroblasts(RARS)
Prussianbluestainofthebonemarrowinapatientwithrefractoryanemiaand
ringsideroblasts(RARS).Bluestainedferritinirondepositsinthemitochondria
oferythroidprecursorsformanapparentringaroundthenucleus(seearrows).
Myelofibrosisbonemarrowbiopsy
Bonemarrowbiopsyinmyelofibrosisshowsreplacementofthemarrowwith
fibroustissue.
Normalbonemarrowbiopsyatlowpower
Lowpowerviewofanormalbonemarrowbiopsy.Theoverallcellularityis
between30and70percent,withtheremainderofthespacebeingoccupied
byfatandstroma.
Bonemarrowbiopsyinprimarymyelofibrosisstainedfor
collagen
Bonemarrowbiopsyfromapatientwithprimarymyelofibrosisstainedfor
collagen(trichromestain).Themarrowcavity(arrows)istraversedbyblue
stainingcollagenbands.
CourtesyofStephenALandaw,MD.
Clumpoftumorcellsinthebonemarrow
Bonemarrowaspiratefromapatientwithcarcinomametastatictothebone
marrow,illustratingthepresenceofalargeclumpoftumorcells(arrow),
surroundedbynormalmarrowelements.Notethatthecellularoutlineswithin
theclumpoftumorcellsareindistinct.Thisisnotacharacteristicofanygroup
ofcellsnormallyseeninthebonemarrow.
CourtesyofDavidSRosenthal,MDandAnnaJMitus,MD.
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.
Conflictofinterestpolicy

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3/4/2017 ApproachtotheadultwithunexplainedthrombocytopeniaUpToDate

Neutrophils <LLNto 1000to 500to <500/microL

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

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

Lymphocytes <LLNto 500to 200to <200/microL

CD4count <LLNto 200to 50to <50/microL

Febrile ANC Lifethreatening Death

VitaminA 500mcg Multivitaminswith

Iron 10mg TIBC,ferritin,

Folicacid 400mcg RBCfolate

Zinc Male:11mg Zincdeficiencymaybe

Copper 2mg Serumcopper

Calciumcitrate 1200to1500 Elementalcalcium 25 Calciumcitrate

VitaminD3 800unitsper Tablets,capsules:400,

Ferrous 40to65mg Combination(eg, Ironstudies, Ironsupplementation

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

Intranasalspray 500mcgonce 500mcgper0.1mL

Intramuscular 1000mcgIM 1000mcgpermL

Overviewof Mucocutaneousbleeding Deeptissuebleeding

Excessive Yes Notusually

Petechiae Common Uncommon

Ecchymoses Generallysmallandsuperficialmaybesignificant, Maydeveloplarge

Hemarthroses, Uncommon Commoninseveredeficiency

Bleedingwith Oftenimmediate,withdegreeofbleedingdependent Maybeassociatedeitherwith

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