Approachtothepatientwiththrombocytopenia

Overview&Recommendations
Background

Thrombocytopeniaisdefinedasplateletcount<2.5thpercentileofnormalplateletcountrange,with
thetraditionalcutoffforthelowerlimitbeing150103/mcL.
Theincidenceofthrombocytopeniarangesfrom8%to68%uponadmissionand13%to44%during
hospitalstay,dependingonthespecificclinicalsetting,patientprofile,andplateletcutoff.
Pathogenicmechanismsofthrombocytopeniaincludedecreasedplateletproduction(forexample,
duetoinfection),increasedplateletdestruction(forexample,duetodruginducedimmune
thrombocytopenia),andothermechanismssuchassplenicsequestration.
Distinguishingsymptomaticvs.asymptomaticthrombocytopeniamayguidediagnosisand
management.

Generalworkup

Historyincludesassessmentofanyfamilyhistoryandreviewofbleeding(includingspecific
bleedingsites,suchasgumbleeding),bruising,petechiae,drugs,vaccines,diet,recenttravels,and
complaintofheadache.
Physicalexamincludesevaluationofskinandpalateforbruisingandpetechiae(petechiaeonthe
palatemaybeassociatedwithhigherriskofspontaneousbleedinginseverethrombocytopenia)and
assessmentoforganomegaly,skeletalabnormalities,andbleedingifpresent.
Diagnostictesting:
Typicallydiagnostictestsincludeacompletebloodcellcountwithwhitebloodcell
differential,peripheralbloodsmear(consideredcentraltoguidingthediagnosticapproachto
thrombocytopenia),liverandrenalfunctiontests,clottingscreenwithDdimers,and
measurementoflactatedehydrogenase.
Incriticallyillpatients,themostimportantinformationtoobtainfromthebloodsmear
includesanevaluationofredbloodcell(RBC)fragmentationtoidentifymicroangiopathyand
assessmentofblaststoidentifyleukemia.
Thereviewoftheperipheralbloodsmearshouldincludecarefulevaluationoffindingsfrom
platelets,whitebloodcells,andredbloodcells.
Themechanismofthrombocytopenia(hypoproductionvs.hyperdestruction)maybe
determinedbyplateletmorphologyfromtheperipheralbloodsmearorbyassessmentofthe
percentagereticulatedplateletcount.

Evaluationbyclinicalsetting
Foroutpatients:
Ifthepatientisbleeding,consideratransfusionandreviewmedicationsorconditionsthatmay
decreaseplateletactivity.
Ifthepatienthasaplateletcount<1020103/mcL:
Suspectimmunethrombocytopenia(ITP),sinceitisfrequentlyacauseofisolatedsevere
thrombocytopenia.
Thereisanincreasedriskofspontaneousbleeding,buttransfusioniscontraindicatedfor
patientswhoaresuspectedofhavingthrombocytopenicpurpura(TTP)/hemolyticuremic
syndrome(HUS),exceptincasesoflifethreateningbleeding.
 Considerothercausesincludinginfections,drugs,orpseudothrombocytopenia.
Ifthepatienthasmultiplecytopenias,consideradditionalworkupforTTP,myelodysplastic
syndrome,leukemia(forexample,chroniclymphocyticleukemia),primarymyelofibrosis,
Evansyndrome,liverdysfunction,drugs,orvitaminB12deficiency.
Ifthepatientshasmildtomoderate(plateletcount>20103/mcL)incidental
thrombocytopeniainabsenceofothercytopenias,considerinfection,hypersplenism,ITP,or
drugs(includingalcohol,illicitsubstances,chemotherapy,protonpumpinhibitors,or
nonsteroidalantiinflammatorydrugs[NSAIDs]).
Bleedinginpatientswithmildtomoderatethrombocytopeniamaysuggestaconcurrent
plateletfunctiondefectorcoagulopathy.
Forhospitalizedpatients:
Considerinfectionasacause,especiallysepsis.
Inpatientswithrecentexposuretoheparin,considerheparininducedthrombocytopenia(HIT).
Othercausesofthrombocytopeniaincludebleedingand/orthrombosis,acuteorchronic
disseminatedintravascularcoagulation(DIC),drugs(especiallyincasesofmultilineage
cytopenias),andposttransfusionpurpura(PTP).
Specialcircumstancesrequiringspecificworkupincludepatientshavingcardiacsurgery,cancer
patients,andpostpartumpatients.

Management
Forcasesofsuspectedheparininducedthrombocytopenia(HIT),heparinshouldbestoppedanda
fulldosealternativeanticoagulantstartedwhilewaitingforlaboratorytestresults(Strong
recommendation).
Transfusioniscontraindicatedforpatientswiththromboticthrombocytopenicpurpura
(TTP)/hemolyticuremicsyndrome(HUS)orHIT,exceptincasesoflifethreateningbleeding
episode.
Forcasesofsuspecteddruginducedthrombocytopenia(DITP),theimplicateddrugshouldbe
stoppedimmediatelyandtheplateletcountshouldbemonitoreduntilitreturnstonormallevels
(Strongrecommendation).
Considerplatelettransfusionforpatientswithseverethrombocytopenia(Strong
recommendation).
Corticosteroidshavenotbeenshowntobeeffectiveinthissetting.
Offerprophylacticplatelettransfusionofupto1apheresisunitorequivalenttoreduceriskof
spontaneousbleedinginhospitalized,adultpatientswithplateletcount10103/mcL(Strong
recommendation).
Considerprophylactictransfusionforpatientswith:
plateletcount<20103/mcLwhoplantohaveelectivecentralvenouscatheterplacement
(Weakrecommendation)
plateletcount<50103/mcLwhoplantohavemajorelectivenonneuraxialsurgeryor
electivediagnosticlumbarpuncture(Weakrecommendation)
Prophylactictransfusionforplateletcount<80103/mcLisoftenrecommendedforneuraxial
surgery,althoughtheexactthresholdiscontroversialwithlittlesupportingdata.
Responsetoplatelettransfusionistypicallymonitored1060minutesaftertransfusionwith
expectationofplateletcountincreasingbyincrementsofapproximately5,00010,000/mcLforeach
randomdonorplatelet(RDP)giveninanaveragesizedadult(70kg[154.3lbs]).

RelatedSummaries
Immunethrombocytopenia(ITP)
Thromboticthrombocytopenicpurpura(TTP)
Heparininducedthrombocytopenia
Hemolyticuremicsyndrome(HUS)

GeneralInformation
Definitions

thrombocytopeniadefinedasplateletcount<2.5thpercentileofnormalplateletcountrange(1)
traditionalcutoffforlowerlimitis150103/mcL
100103/mcLcutoffmaybemoreappropriatetoidentifyspecificpathologiccondition
cutoff<150103/mcLmayalsobemoreappropriateinnonWesterncountries
thrombocytopeniaseveritybasedonplateletcount(3)
mild=70150103/mcL
severe=<20103/mcL
expectedsymptomsbasedonplateletcount(3)
>50103/mcLoftenasymptomatic
3050103/mcLmayhaveexcessivebleedingwithtrauma
1030103/mcLmayhaveexcessivebleedingwithminimaltrauma
<10103/mcLincreasedriskofspontaneousbleeding
<5103/mcLhighriskofspontaneousbleeding,hematologicemergency

Incidenceandprevalence

incidenceofthrombocytopeniainintensivecareunitrangesfrom8%to68%uponadmissionand
13%to44%duringhospitalstaydependingonspecificsetting,patientprofile,andplateletcutoff(1)
druginducedimmunethrombocytopenia(1,2)
overallincidenceabout10casespermillionpersonsperyear
occursinabout20%25%ofcriticallyillpatients
heparininducedthrombocytopeniaoccursin0.5%5%ofpatientstreatedwithheparinbutonly
accountsfor<1%ofcasesofthrombocytopeniainintensivecaresetting(1)
pseudothrombocytopenia(artifactualplateletclumping)occursin1in1,000patientsandiscausedby
invitroagglutinationduetoethylenediaminetetraaceticacidinsamplecollectingtubes(3)

EtiologyandPathogenesis
Causesofthrombocytopeniabymechanism

Decreasedplateletproduction

bonemarrowfailure(forexample,aplasticanemiaorprimarymyelofibrosis)(3)
neoplasticmarrowinfiltration(3)
bonemarrowsuppressionfromchemotherapy,medication,orirradiation(3)
chronicalcoholabuse(3)
congenitalmacrothrombocytopenias(forexample,Alportsyndrome)(3)
infection(3)
viralinfections,suchasHIV,hepatitisBandhepatitisC,cytomegalovirus(CMV),Epstein
Barrvirusassociatedinfectiousmononucleosis,parvovirusB19infection,andvaricellazoster
rickettsialinfections,suchasLymedisease,RockyMountainspottedfever,orehrlichiosis
Helicobacterpylori
myelodysplasticsyndrome(3)
nutritionaldeficiencies(forexample,invitaminB12orfolate)(3)

Increasedplateletdestruction

alloimmunedestruction,eitherposttransfusionorposttransplantation(3)
autoimmunesyndromes,suchsystemiclupuserythematosus(SLE),rheumatoidarthritis(RA),
antiphospholipidantibodysyndrome,orsarcoidosis(1,3)
chronicandacutedisseminatedintravascularcoagulation(DIC)asseenwithseveresepsis(3)
druginducedimmunethrombocytopenia
fulllistofdrugswithpotentialforthrombocytopeniaislongandconstantlyexpanding,
particularlyfornewdrugsthatdonothaveanestablishedadverseeventprofile(1)
drugsimplicatedinacuteimmunethrombocytopenia,establishedby3separatemethods(case
reportsinliterature,referencelaboratorytestingofpatients'serafordrugdependent
antibodies,anddatamininginUnitedStatesDepartmentofAgriculture[USDA]Adverse
EventReportingSystemdatabase)
abciximab
acetaminophen
ampicillin
carbamazepine
eptifibatide
ethambutol
haloperidol
ibuprofen
irinotecan
naproxen
oxaliplatin
phenytoin
piperacillin
quinidine
quinine
ranitidine
rifampin
simvastatin
sulfisoxazole
tirofiban
sulfamethoxazoletrimethoprim
valproicacid
vancomycin
ReferenceBlood2010Sep23116(12):2127fulltext,commentarycanbefoundin
Blood2010Sep23116(12):2002fulltext
establishedcriteriaforimplicatingadrugsuspectedofcausingdruginducedimmune
thrombocytopenia
1.thrombocytopeniawasprecededbyexposuretocandidatedrug
2.upondiscontinuationofcandidatedrug,plateletcountrecoversandsustainswithin
normalrange(recoverymaytakeweekstomonths)
3.eithercandidatedrugwasonlydrugadministeredpriortothrombocytopeniaORother
drugswerecontinuedorreintroducedafterdiscontinuationofcandidatedrugfollowed
bysustained,normalplateletcount
4.othercausesofthrombocytopeniaexcluded
5.recurrentthrombocytopeniauponreexposureofcandidatedrug
gradingofevidenceforcasualassociation
definiteif1,2,3,and4aremet
probableif1,2,and3aremet
possibleifonly1ismet
unlikelyif1isnotmet
ReferenceAnnInternMed1998Dec1129(11):886
medicationsassociatedwiththromboticthrombocytopenicpurpura(TTP)include
chemotherapyagentssuchasgemcitabineandmitomycinC
immunosuppressivedrugssuchastacrolimusandcyclosporine
thrombocytopeniafollowingmeasles,mumps,rubella(MMR)vaccinehasareportedincidence
of1in25,00040,000doses(PaediatrChildHealth2009Jan14(1):31fulltext)
 illicitdruguse,specificallyheroinandcocainethatareoftencutwithquinine,levamisole,and
otherknownagentsofdruginducedimmunethrombocytopenia(2)
foodandherbalremedies
food,beverages,andherbalremediesimplicatedinthrombocytopeniaincasereports
meetingcriteriafordefiniteevidenceforcausalassociationinclude
cow'smilk
cranberryjuice
Juiherbaltea
Lupinustermisbean(whitebeangrowninNorthAfricaandMediterranean
regions)
tahini
ReferenceEurJHaematol2010May84(5):421
walnutsreportedascausativeagentofdruginducedimmunethrombocytopeniaincase
report(Lancet2012Feb25379(9817):776fulltext)
heparininducedthrombocytopenia
immunethrombocytopenia(ITP)
infection(usuallyduetobonemarrowsuppression)(3)
viralinfections,suchasHIV,hepatitisBandhepatitisC,cytomegalovirus(CMV),Epstein
Barrvirusassociatedinfectiousmononucleosis,parvovirusB19infection,andvaricellazoster
rickettsialinfections,suchasLymedisease,RockyMountainspottedfever,orehrlichiosis
Helicobacterpylori
mechanicaldestruction(forexample,fromextracorporealbypass)(3)
HELLPsyndrome(hemolysis,elevatedliverenzymes,andlowplateletcount)orpreeclampsia(3)
thromboticthrombocytopenicpurpura(TTP)/hemolyticuremicsyndrome(HUS)

Othermechanismsofthrombocytopenia

plateletsequestrationduetohypersplenism(1,3)
hemodilutionaftertreatmentwithcolloids,crystalloids,orplateletpoorproductsafteramassive
bleedingepisode(1,3)
pseudothrombocytopenia(artifactualplateletclumping)(3)
gestationalthrombocytopenia(1,3)
pulmonaryemboli(3)
pulmonaryhypertension(3)

Pathogenesisofprimarymechanisms

decreasedplateletproduction(3)
myelosuppressivetreatments(forexample,chemotherapyorradiationtherapy)reduce
productionofnewplatelets
chronicalcoholabuseleadstoliverdiseasethatresultsindirecttoxicmarrowsuppressionand
splenicsequestration
increasedplateletdestruction(2)
inimmunethrombocytopenia,autoantibodiesbindanddirectplateletsfordestructionand
clearance,usuallybyreticuloendothelialsystem
indruginducedimmunethrombocytopenia
inmostcases,plateletdestructionmediatedbyautoantibodytargeting(usually
glycoproteinonsurface)thatrequirespresenceofdrug
insomecases,certaindrugs(forexample,goldsaltsandprocainamide)stimulate
productionoftrueautoantibodiesthatdonotrequiredrugtotargetplatelets
inheparininducedthrombocytopenia,patientsdevelopantibodiestoplateletfactor4in
complexwithheparin,resultinginthrombocytopeniaandclinicallysignificantthrombosis

GeneralWorkup
History

askabout
familyhistoryofthrombocytopeniatoevaluateforcongenitalthrombocytopenia(1,3)
bleedinghistory,includinganysuddenchangesinbleeding
gumbleedingwithminortrauma(brushingteeth)isaverysensitiveindicatorof
increasedbleedingrisk(AmFamPhysician2010Dec182(11):1381fulltext)
menorrhagiamaybepresentinwomenwithessentialthrombocytopeniaorvon
Willebranddisease(AmJObstetGynecol1996Sep175(3Pt2):770)
hematuriapresentinupto90%ofpatientswiththromboticthrombocytopenicpurpura
(TTP)(Hematology2006Jun11(3):139)
easybruisingorpetechiae(3)
mildthrombocytopeniaandmucocutaneousbleedingmayindicatevonWillebrand
diseasetype2B(Blood2015Mar26125(13):2029fulltext)
historyofpotentialdiseasecauses(forexample,autoimmunedisorders,infections,or
malignancies)
drughistory
evaluatetemporalprofilethatmayindicatedruginducedimmunethrombocytopenia
suggestiveprofileincludesdecreaseinplateletsoccurring23dayswithintakingdrug
thathasbeentakenpreviously(insomecasesmayoccurwithinafewhours),or13
weeksafterstartinganewdrug
vaccinationhistory,includingrecentimmunizationwithmeasles,mumps,rubella(MMR),
varicella,andinfluenzaA(H1N1)vaccines
othermedicalhistory,suchasrecenthospitalizationorrecentvalvereplacementsurgery
diet,includingconsumptionofalcoholandquininecontainingbeverages
socialfactors,including
riskfactorsforretroviralinfectionsandviralhepatitis
illicitdruguse,specificallycocaineandheroin
recenttravels,toassessriskassociatedwithmalaria,rickettsialinfection,ordenguefever
complaintofheadache,whichmaypromptneuroimagingtoruleoutintracranialbleeding
casereportofheadacheasapresentingsymptominpatientwithintracranialbleedand
thrombocytopeniacanbefoundinJSurgTechCaseRep2012Jul4(2):132

Physicalexam

assessskinandpalateforbruising,purpura,andpetechiaepetechiaeonthepalatemaybeassociated
withhigherriskofspontaneoushemorrhageinseverethrombocytopenia
lookfor(1)
organomegaly
skeletalabnormalitiesincludingabsenceoflongthinbonesofforearmsassociatedwithrare
autosomalrecessivedisorderthrombocytopeniaabsentradius(TAR)reviewedinAnnMed
2014Sep46(6):353fulltext
assessbleedingifpresent(1,2,3)
mucocutaneousbleedingistypical,butepistaxisorgastrointestinalbleedingmayalsooccur
jointorsofttissuebleedingassociatedwithdisruptedcoagulation
ischemiclimbofskinnecrosiscanindicateheparininducedthrombocytopenia
petechiae,bruising,andnosebleedarecommonindruginducedimmunethrombocytopenia

Diagnostictesting

allpatientsshouldhavecompletebloodcountwithwhitebloodcelldifferentialandevaluationof
peripheralbloodsmear(1)
additionaltestingtoconsideratinitialevaluation(1)
liverfunctiontests,whichareabnormalincasesofliverdiseasesuchascirrhosisoftheliver
renalfunctiontests,whichareabnormalinconditionsassociatedwithkidneydamage,suchas
thromboticthrombocytopenicpurpura(TTP)orhemolyticuremicsyndrome(HUS)
 clottingscreenwithDdimers,whichareelevatedincasesofpulmonaryembolismor
disseminatedintravascularcoagulation(DIC)
measurementoflactatedehydrogenase,whichareelevatedincasesofthrombotic
thrombocytopenicpurpura(TTP)andotherdisorders,suchasliverdisease,Evan'ssyndrome,
andsomeautoimmunedisease(especiallythosewithliverinvolvement)
peripheralbloodsmeariscentraltoguidingdiagnosticapproachtothrombocytopenia,andall3
bloodcelllineagesshouldbeevaluatedcarefully(1,3)
whenevaluatingthrombocytopeniaincriticallyillpatient,mostimportantinformationto
obtainfrombloodsmearincludesevaluationofredbloodcell(RBC)fragmentationtoidentify
microangiopathyandassessmentofblaststoidentifyleukemia
plateletfindings
plateletclumpingsuggestspseudothrombocytopenia(artifactualthrombocytopenia
causedbyinvitroagglutinationduetoethylenediaminetetraaceticacidinsample
collectingtubes)
plateletsize
consistentlylargeplateletssuggesthereditarymacrothrombocytopenialarge
plateletswithgraycoloronWrightGiemsastaindefine"grayplateletsyndrome"
anautosomaldominantmacrothrombocytopeniaassociatedwithbleedingand
causedbyabsentorsubstantiallyreducedalphagranules
smallplateletssuggestWiskottAldrichsyndromeorXlinkedthrombocytopenia
megakaryocytefragmentstogetherwithlargeplateletssuggestprimarymyelofibrosis
hypogranularplateletssuggestmyelodysplasticsyndromeorprimarymyelofibrosis
whitebloodcellfindings
identificationofblastssuggestleukemiaorlymphoma
hypolobulatedneutrophils(PelgerHuetanomaly)suggestmyelodysplasticsyndrome
darkcoarsegranulessuggestsepsis
atypicallymphocytessuggestviralinfection(forexample,cytomegalovirusinfection)
whitebloodcellinclusions(Dohlelikebodies)togetherwithmostlylargeplateletsmay
suggestMYH9relatedcongenitalmacrothrombocytopenia
redbloodcellfindings
ifschistocytespresent,considerTTP/HUSorDIC
nucleatedredbloodcellsorteardropshapedcellssuggestprimarymyelofibrosis
presenceofmicrospherocytessuggestEvansyndrome(autoimmunehemolyticanemia
andthrombocytopenia)consideradditionaltestingforEvansyndromewithdirect
antibodytestandmeasuringreticulocytes,lactatedehydrogenase,andbilirubinlevels,all
ofwhichmaybeelevated(1)
ovalmacrocytosisandhypersegmentedneutrophilssuggestvitaminB12deficiencyor
folatedeficiency
basophilicstippling(bluegranulesindicatingribosomesappearingthroughredblood
cellcytoplasm)suggeststhalassemia,chronicalcoholuse,orleadormetalpoisoning
identificationofparasites(forexample,incasesofmalaria)considereddiagnosticfor
infectiouscause
differentiatinghypoproductionvs.hyperdestructionasmechanismofthrombocytopenia(1)
plateletmorphologyfromperipheralbloodsmearisstandardtechnique
peripheraldestructiontypicallyresultsinplateletsvaryinginsizefromnormaltolarge
orgiant
decreasedplateletproductionafterchemotherapytypicallyresultsinnormallysized
platelets
myelodysplasticsyndromestypicallyresultinvariablysizedplateletsthatareoften
hypogranular
percentagereticulatedplateletcountorequivalentpercentageimmatureplateletcountmayalso
beused,butspecificityofthesetestshasnotbeenprospectivelyvalidated(1)
reticulatedplatelets<11%mayhelpruleouthyperdestructivethrombocytopenia
(level2[midlevel]evidence)
basedondiagnosticcohortstudywithoutindependentvalidation
101patientswiththrombocytopeniahadmeasurementsofreticulatedplateletsby
direct,wholeblood,duallabellingflowcytometryandperipheralbloodsmear
 (referencestandard)
patientswithnormalordecreasedactivityincludedpatientswithdiminished
ordefectiveplateletproductionandpatientswiththrombocytopeniawith
abnormaldistribution
patientswithincreasedactivityincludedpatientswithenhancedplatelet
destructionbyimmunologic(ITP)andnonimmunologicmechanisms
41patients(41%)hadhyperdestructivethrombocytopenia
reticulatedplatelet<11%derivedasoptimalcutoffinreceiveroperator
characteristicanalysis
foridentifyingpatientswithhyperdestructivethrombocytopenia,percentageof
reticulatedplatelets<11%had
sensitivity93%
specificity85%
positivepredictivevalue83%
negativepredictivevalue95%
ReferenceQJM2008Jul101(7):549,fulltext
pooragreementinmeasurementof"youngplatelets"(immatureplateletfractionor
reticulatedplateletfraction)reportedbetweenautomatedhematologyanalyzers(Clin
LabMed2015Mar35(1):209)

ApproachBasedonClinicalSetting
Thrombocytopeniainoutpatient

ifpatientisbleeding,considertransfusionandreviewmedicationsorconditionsthatmaydecrease
plateletactivity(4)
ifpatienthasplateletcount<1020103/mcL
suspectimmunethrombocytopenia(ITP),sinceitisfrequentlyacauseofisolatedsevere
thrombocytopenia
increasedriskofspontaneousbleeding,butdecisiontotransfusepatientswithinthisplatelet
rangeshouldbecarefullyconsidered(3,4)
transfusioniscontraindicatedforpatientspresentinginthisplateletrangewhoaresuspectedof
havingthrombocytopenicpurpura(TTP)/hemolyticuremicsyndrome(HUS)exceptincasesof
lifethreateningbleeding(4)
patientswithTTP/HUSmostcommonlypresentwithabdominalpain,nausea,vomiting,
weakness(3)
considerothercausesincludinginfections,drugs,orpseudothrombocytopenia
ifpatienthasmultiplecytopenias,consideradditionalworkupfor
thromboticthrombocytopenicpurpura(TTP)
myelodysplasticsyndrome
primarymyelofibrosis
chroniclymphocyticleukemia(CLL),especiallyinolderpatients
Evansyndrome(autoimmunehemolyticanemiaandthrombocytopenia)(1)
liverdysfunction(forexample,cirrhosisoftheliver)
drugs
vitaminB12deficiencyaccompanyinganemiaisusuallymoreprominent
aplasticanemia
leukemias(forexample,acutemyeloidleukemia),especiallyifabnormalwhitecellspresent
autoimmunesyndromes,suchassystemiclupuserythematosus(SLE),rheumatoidarthritis
(RA),antiphospholipidantibodysyndrome,orsarcoidosis(1,3)
infection,especiallyifchronicallyill
ifpatientshasmildtomoderate(plateletcount>20103/mcL),incidentalthrombocytopeniain
absenceofothercytopenias,consider
infection
hypersplenism(3)
 immunethrombocytopenia(ITP),althoughITPcanalsopresentwithseverethrombocytopenia
drugs(includingalcohol,illicitsubstances,chemotherapy,protonpumpinhibitors,or
nonsteroidalantiinflammatorydrugs[NSAIDs])(1,2,3)
bleedinginpatientswithmildtomoderatethrombocytopeniamaysuggestconcurrentplatelet
functiondefectorcoagulopathy

Thrombocytopeniainhospitalizedpatient

considerinfection,especiallysepsis(1)
inpatientswithrecentexposuretoheparin,considerheparininducedthrombocytopenia(HIT)(1)
onlyaccountsforabout1%ofcasesofthrombocytopeniaintheintensivecareunit(ICU),but
incidenceishigheramongstcardiacpatients
lowplateletcount(typicallyranges5080103counts/mcL)typicallydevelops510days
afterinitialexposure,butearlieronsetoccursinabout30%ofpatientswithahistoryofheparin
useinlast3months
specificclinicalpresentationmayincludevenousorarterialthrombosis,necroticskinlesionsat
injectionsites,oracutesystemicreactionsafterheparinbyIVbolus
incasesofsuspectedHIT,heparinshouldbestoppedandfulldosealternativeanticoagulant
startedwhilewaitingforlaboratorytestresults
considerothercausesofthrombocytopenia,including
bleedingand/orthrombosis(3)
acutedisseminatedintravascularcoagulation(DIC),especiallyincasesofbleedingandorgan
damage,andmayoccurincasesof(1)
severesepsisandsepticshock
trauma,surgery,orABOincompatiblebloodtransfusion
preeclampsiaoramnioticfluidembolism
acutepromyelocyticleukemia(APL)
chronicDIC(1)
typicallyassociatedwithsolidtumorsandlargeaorticaneurysms
notaccompaniedbytypicalclinicalmanifestationsortestingfindingsforDIC
drugs,especiallyincasesofmultilineagecytopenias(2)
posttransfusionpurpura(PTP)(2)
raredisordersimilartodruginducedthrombocytopenia(DITP)thatoccurs510days
afterbloodtransfusion
becauseofsimilaritiesinclinicalpresentation,differentiatingPTPfromdruginduced
thrombocytopeniamaybedifficultinsituationswherepatientshavereceivedablood
transfusionwhileonmedication
typicallydistinguishedfromDITPbypresenceofplateletspecificantibodies(human
plateletalloantigen1a)inpatientsera

Specialpopulations

Thrombocytopeniaaftercardiacsurgery

heparininducedthrombocytopeniaoccursin1%3%ofpatientsreceivingheparinbeyondfirst
postoperativeweekofcardiacsurgeryandin10%ofpatientspostventricularassistdevice
implantation(1)
thrombocytopeniainducedbyglycoproteinIIb/IIIainhibitors(abciximab,tirofiban,eptifibatide)can
berapidonsetandsevere,occurringwithinhoursofsurgery(1)
reportssuggestabciximabmayalsocausedelayedonsetthrombocytopenia(36daysaftertreatment)
duetoproductionofantibodiesagainstmurineportionofabciximab(1)
cardiopulmonarybypasscancauseplateletdestructionorhemodilutioninadditiontodruginduced
thrombocytopenia(1)
 lessfrequentcausesofthrombocytopeniapostcardiacsurgeryinclude,sepsis,intraaorticballoon
pumping,andposttransfusionpurpura(1)

Thrombocytopeniaincancerpatients

usuallyattributedtobonemarrowsuppression(2)
severalchemotherapeuticagentshavebeenimplicatedincasesofdruginducedimmune
thrombocytopenia(forexample,oxaliplatin)(2)
rateofthrombocytopeniainpatientstreatedwithchemotherapyestimatedtobe21%70%(2)

Thrombocytopeniainpregnantorpostpartumpatients

gestationalthrombocytopenia(3)
mildthrombocytopeniaoccursin8%ofpregnanciesandspontaneouslyresolvesafterdelivery
benignclinicalconditionthoughttobecausedbyhemodilutionandacceleratedplatelet
clearance
othercausesincludehemolysis,elevatedliverenzymes,lowplatelets(HELLP)syndromeand
preeclampsia(3)

Management
Causespecificmanagement

incasesofsuspectedheparininducedthrombocytopenia(HIT),heparinshouldbestoppedandfull
dosealternativeanticoagulantstartedwhilewaitingforlaboratorytestresults(1)
treatmentofpatientswithdruginducedthrombocytopenia(DITP)involves(2)
immediatestoppingofimplicateddrugandmonitoringplateletcountuntilreturnofnormal
levels
patientswithseverethrombocytopeniaorbleedingmayrequireplatelettransfusions
unlikeimmunethrombocytopenia,corticosteroidshavenotbeenshowntobeeffective
treatmentforDITP

Platelettransfusion

guidanceforplatelettransfusion(4,5)
AmericanRedCrosssuggestsplatelettransfusionofrandomdonorplatelets(RDPs)totreat
patientswhoarebleedingwith410unitsofRDPsbeingtypicaldoseforaverageadultpatient
(70kg[154.3lbs])withthrombocytopenia
AABBrecommendsprophylacticplatelettransfusionofupto1apheresisunitorequivalentto
reduceriskofspontaneousbleedinginhospitalized,adultpatientswithplateletcount10X
103/mcL(AABBStrongrecommendation,Moderatequalityevidence)
transfusioniscontraindicatedforpatientswiththromboticthrombocytopenicpurpura
(TTP)/hemolyticuremicsyndrome(HUS)orheparininducedthrombocytopenia(HIT),except
incasesoflifethreateningbleedingepisode
guidanceforprophylactictransfusionpriortosurgeryorplannedprocedure(4,5)
AmericanRedCrosssuggestsprophylactictransfusiontomaintaincount
>50X103/mcLinpatientswithplannedinvasiveprocedureorsurgerywhenindicated
>100x103/mcLinpatientswithplannedneurologicorophthalmologicprocedure
AABB(formerly,theAmericanAssociationofBloodBanks)suggestsprophylacticplatelet
transfusionforpatientswithplateletcount<20103/mcLwhoplantohaveelectivecentral
venouscatheterplacement(AABBWeakrecommendation,Lowqualityevidence)
AABBsuggestsprophylacticplatelettransfusionforpatientswithplateletcount<50
103/mcLwhoplantohavemajorelectivenonneuraxialsurgeryorelectivediagnosticlumbar
 puncture(AABBWeakrecommendation,Verylowqualityevidence)
prophylactictransfusionforplateletcount>80103/mcLoftenrecommendedforneuraxial
surgery,althoughexactthresholdiscontroversialwithlittlesupportingdata
responsetoplatelettransfusion
AmericanRedCrosssuggestsmonitoringresponse1060minutesaftertransfusionwith
expectationofplateletcountincreasingbyincrementsofapproximately5,00010,000/mcLfor
eachRDPgiveninaveragesizedadult(70kg[154.3lbs])(4)
platelettransfusionrefractoriness(PTR)occurswhenpatient'splateletcountdoesnotriseto
expectedlevelsinspiteofmultipleplatelettransfusions(2)
canbedifficulttodistinguishfromDITPinpatientsreceivingbothplateletsanddrugs
knowntocauseDITP
immuneformsofPTRcanbeidentifiedbypresenceofhumanleukocyteantigen(HLA)
andplateletspecificantibodies
carefulrecordingofplateletcountafterdiscontinuingcandidatedrugmaybenecessary
inchallengingcasesornonimmunePTR(bonemarrowsuppression,fever,sepsis)

Romiplostim
generalinformation
thrombopoietinreceptoragonist,typicallyusedforpersistentorchronicimmune
thrombocytopenia(JBloodMed20156:37)
dosingbasedonplateletcount
if>200103/mcLfor2consecutiveweeks,reducedoseby1mcg/kg
if>400103/mcL,doNOTdoseandmonitorweeklyplateletcounts
ReferenceAmJHealthSystPharm2009May166(9):817
romiplostimreportedtoincreasepreoperativeplateletcountsinpatientswith
thrombocytopenia(level3[lackingdirect]evidence)
basedoncaseseries
18patients(including3Jehovah'switnesseswhochosetoavoidbloodtransfusion)underwent
22operativeprocedures(including6orthopedic,4cardiac,5gastrointestinal)
thrombocytopeniaetiologiesincludedmildimmunethrombocytopenia,liverdisease,
hematologicmalignancy,anddruginducedthrombocytopenia
plateletcountsbeforestartofromiplostim
<50103/mcLfor11patients
between50and100103/mcLfor5patients
>100103/mcLfor2patients
medianplateletincreaseabout100103/mcLovermedianof4weeksinoverallanalysis
ReferenceTransfusion2015Oct55(10):2505

GuidelinesandResources
Guidelines

AmericanAssociationofBloodBanks(AABB)clinicalpracticeguidelineonplatelettransfusioncan
befoundinAnnInternMed2015Feb3162(3):205fulltextoratNationalGuidelineClearinghouse
2015Oct12:49247

AmericanRedCrosspracticeguidelinesontransfusioncanbefoundinAmericanRedCross2013
PDF

Reviewarticles
reviewofdiagnosisofimmunemediatedthrombocytopeniacanbefoundinAutoimmunRev2014
AprMay13(45):577
 reviewofmanagementofimmunethrombocytopeniacanbefoundinHematologyAmSocHematol
EducProgram20132013:276fulltext
reviewofdiagnosisandmanagementofdruginducedthrombocytopeniacanbefoundinTransfus
MedRev2013Jul27(3):137fulltext
reviewofthromboticthrombocytopeniapurpuracanbefoundinAutoimmunRev2014Apr
May13(45):584
reviewofheparininducedthrombocytopeniacanbefoundinHematologyAmSocHematolEduc
Program20132013:668fulltext
reviewofthrombocytopeniainpregnancycanbefoundinHematologyAmSocHematolEduc
Program20102010:397fulltext

PatientInformation
handoutfromMayoClinic
handoutfromClevelandClinic

ICD9/ICD10Codes
ICD9codes
287.3primarythrombocytopenia
287.30primarythrombocytopenia,unspecified
287.31immunethrombocytopenicpurpura
287.32Evans'syndrome
287.33congenitalandhereditarythrombocytopenicpurpura
287.39otherprimarythrombocytopenia
446.6thromboticthrombocytopenicpurpura
289.84heparininducedthrombocytopenia(HIT)
995.29unspecifiedadverseeffectofotherdrug,medicinalandbiologicsubstance

ICD10codes

D69.3idiopathicthrombocytopenicpurpura
ICD10CAmodificationinCanada:D69.3subdividedtoidentify
D69.30Evans'syndrome
D69.38otheridiopathicthrombocytopenicpurpura
D69.4otherprimarythrombocytopenia
M31.1thromboticmicroangiopathy
D75.82heparininducedthrombocytopenia(HIT)

References
Generalreferencesused
1.StasiR.Howtoapproachthrombocytopenia.HematologyAmSocHematolEducProgram.
20122012:1917fulltext
2.CurtisBR.Druginducedimmunethrombocytopenia:incidence,clinicalfeatures,laboratory
testing,andpathogenicmechanisms.Immunohematology.201430(2):5565
3.GauerRL,BraunMM.Thrombocytopenia.AmFamPhysician.2012Mar1585(6):61222full
text
4.ACompendiumofTransfusionPracticeGuidelines.Secondedition.AmericanRedCross2013
PDF
5.KaufmanRM,DjulbegovicB,GernsheimerT,etal.Platelettransfusion:aclinicalpractice
guidelinefromtheAABB.AnnInternMed.2015Feb3162(3):20513
Recommendationgradingsystemsused

AABB(formerly,theAmericanAssociationofBloodBanks)guidelinegradingsystem
strengthofrecommendation
Strongbenefitsclearlyoutweighrisksandburden,orrisksandburdenclearlyoutweigh
benefits
Weakbenefitsfinelybalancedwithrisksandburden
qualityofevidence
Highfurtherresearchveryunlikelytochangeconfidenceinestimateofeffect
Moderatefurtherresearchlikelytohaveimportantimpactonconfidenceinestimateof
effectestimatemaychange
Lowfurtherresearchverylikelytohaveimportantimpactonconfidenceinestimateof
effectestimatewilllikelychange
Verylowanyestimateofeffectveryuncertain
ReferenceAABBclinicalpracticeguidelineonplatelettransfusion(AnnInternMed2015
Feb3162(3):205fulltext)

SynthesizedRecommendationGradingSystemforDynaMedPlus

DynaMedsystematicallymonitorsclinicalevidencetocontinuouslyprovideasynthesisofthemost
validrelevantevidencetosupportclinicaldecisionmaking(see7StepEvidenceBased
Methodology).
GuidelinerecommendationssummarizedinthebodyofaDynaMedtopicareprovidedwiththe
recommendationgradingsystemusedintheoriginalguideline(s),andallowDynaMedusersto
quicklyseewhereguidelinesagreeandwhereguidelinesdifferfromeachotherandfromthecurrent
evidence.
InDynaMedPlus(DMP),wesynthesizethecurrentevidence,currentguidelinesfromleading
authorities,andclinicalexpertisetoproviderecommendationstosupportclinicaldecisionmakingin
theOverview&Recommendationssection.
WeusetheGradingofRecommendationsAssessment,DevelopmentandEvaluation(GRADE)to
classifysynthesizedrecommendationsasStrongorWeak.
Strongrecommendationsareusedwhen,basedontheavailableevidence,clinicians(without
conflictsofinterest)consistentlyhaveahighdegreeofconfidencethatthedesirable
consequences(healthbenefits,decreasedcostsandburdens)outweightheundesirable
consequences(harms,costs,burdens).
Weakrecommendationsareusedwhen,basedontheavailableevidence,cliniciansbelieve
thatdesirableandundesirableconsequencesarefinelybalanced,orappreciableuncertainty
existsaboutthemagnitudeofexpectedconsequences(benefitsandharms).Weak
recommendationsareusedwhencliniciansdisagreeinjudgmentsofrelativebenefitandharm,
orhavelimitedconfidenceintheirjudgments.Weakrecommendationsarealsousedwhenthe
rangeofpatientvaluesandpreferencessuggeststhatinformedpatientsarelikelytomake
differentchoices.
DynaMedPlus(DMP)synthesizedrecommendations(intheOverview&Recommendationssection)
aredeterminedwithasystematicmethodology:
Recommendationsareinitiallydraftedbyclinicaleditors(including1withmethodological
expertiseand1withcontentdomainexpertise)awareofthebestcurrentevidencefor
benefitsandharms,andtherecommendationsfromguidelines.
Recommendationsarephrasedtomatchthestrengthofrecommendation.Strong
recommendationsuse"shoulddo"phrasing,orphrasingimplyinganexpectationtoperform
therecommendedactionformostpatients.Weakrecommendationsuse"consider"or
"suggested"phrasing.
RecommendationsareexplicitlylabeledasStrongrecommendationsorWeak
recommendationswhenaqualifiedgrouphasexplicitlydeliberatedonmakingsucha
recommendation.Groupdeliberationmayoccurduringguidelinedevelopment.Whengroup
deliberationoccursthroughDynaMedinitiatedgroups:
ClinicalquestionswillbeformulatedusingthePICO(Population,Intervention,
Comparison,Outcome)frameworkforalloutcomesofinterestspecifictothe
recommendationtobedeveloped.
 Systematicsearcheswillbeconductedforanyclinicalquestionswheresystematic
searcheswerenotalreadycompletedthroughDynaMedcontentdevelopment.
Evidencewillbesummarizedforrecommendationpanelreviewincludingforeach
outcome,therelativeimportanceoftheoutcome,theestimatedeffectscomparing
interventionandcomparison,thesamplesize,andtheoverallqualityratingforthebody
ofevidence.
Recommendationpanelmemberswillbeselectedtoincludeatleast3membersthat
togetherhavesufficientclinicalexpertiseforthesubject(s)pertinenttothe
recommendation,methodologicalexpertisefortheevidencebeingconsidered,and
experiencewithguidelinedevelopment.
Allrecommendationpanelmembersmustdiscloseanypotentialconflictsofinterest
(professional,intellectual,andfinancial),andwillnotbeincludedforthespecificpanel
ifasignificantconflictexistsfortherecommendationinquestion.
PanelmemberswillmakeStrongrecommendationsifandonlyifthereisconsistent
agreementinahighconfidenceinthelikelihoodthatdesirableconsequencesoutweigh
undesirableconsequencesacrossthemajorityofexpectedpatientvaluesandpreferences.
PanelmemberswillmakeWeakrecommendationsifthereislimitedconfidence(or
inconsistentassessmentordissentingopinions)thatdesirableconsequencesoutweigh
undesirableconsequencesacrossthemajorityofexpectedpatientvaluesandpreferences.
Norecommendationwillbemadeifthereisinsufficientconfidencetomakea
recommendation.
Allstepsinthisprocess(includingevidencesummarieswhichweresharedwiththe
panel,andidentificationofpanelmembers)willbetransparentandaccessibleinsupport
oftherecommendation.
Recommendationsareverifiedby1editorwithmethodologicalexpertise,notinvolvedin
recommendationdraftingordevelopment,withexplicitconfirmationthatStrong
recommendationsareadequatelysupported.
Recommendationsarepublishedonlyafterconsensusisestablishedwithagreementin
phrasingandstrengthofrecommendationbyalleditors.
Ifconsensuscannotbereachedthentherecommendationcanbepublishedwithanotationof
"dissentingcommentary"andthedissentingcommentaryisincludedinthetopicdetails.
Ifrecommendationsarequestionedduringpeerrevieworpostpublicationbyaqualified
individual,orreevaluationiswarrantedbasedonnewinformationdetectedthroughsystematic
literaturesurveillance,therecommendationissubjecttoadditionalinternalreview.

DynaMededitorialprocess
DynaMedtopicsarecreatedandmaintainedbytheDynaMedEditorialTeamandProcess.
Alleditorialteammembersandreviewershavedeclaredthattheyhavenofinancialorother
competinginterestsrelatedtothistopic,unlessotherwiseindicated.
DynaMedprovidesPracticeChangingDynaMedUpdates,withsupportfromourpartners,McMaster
UniversityandF1000.

Specialacknowledgements

E.DiannePulte,MD(ClinicalAssistantProfessorofHematologyandDirectorofSickleCell
DiseaseCenter,ThomasJeffersonUniversityPennsylvania,UnitedStates)
Dr.PultedeclaresreceivingfinancialcompensationfromApoPharma,Quintiles/Selexys,and
ThomasJeffersonUniversity.

Howtocite
ForattributioninotherpublicationsseeHowtoCiteInformationfromDynaMed.