BLEEDING(PLATELET)DISORDER

IAPUGTeachingslides201516 1
 APPROACH

Theinitialsetofquestionsshouldestablishthe
following:

(1)themostcommonsiteandtypeofbleeding(e.g.,
mucocutaneousversusarticularordeepmuscle),

(2)bleedingonhemostaticchallengesuchassurgeries
ortrauma,and

(3)familyhistoryofbleeding.
IAPUGTeachingslides201516 2
Clinical PrimaryHemostatic ClottingFactor
Characteristic Defect Deficiency
Siteofbleeding Skin,mucous Softtissues,muscles,
membranes joints

Bleedingafter Yes Rare

minorcuts
Petechiae present absent
Ecchymosis Small,superficial Large,deep,
palpable
Hemarthrosis Rare Common
Bleedingafter Immediate Delayed
trauma/surgery

IAPUGTeachingslides201516 3
PLATELETINVASCULARINJURY

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 HISTORY

Largebruiseswithoutprevioussignificanttrauma,
disseminatedpetechiae,intramuscularhematomas,
hemarthrosis(jointeffusion,warmth,andpainwith
passivemovement)usuallyindicateableeding
disorder

Inyoungchildren,refusaltowalkisoftenasignfor
anextremityrelatedbleedandcouldrepresentthe
firstsignofhemarthrosisinaboywithhemophilia
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 HISTORY

Symptomsofbleedingdisorders,couldbeeasybruisingand
mucosalbleeding(e.g.Epistaxis,menorrhagia,oropharyngeal)

Inflictedtraumaismostlikelytomanifestoverthehead,
chest,back,andlongbones(andmayretaintheoutlinesof
theinstrumentusedtoinflictharm),whereasbruises
associatedwithprimaryhemostasisdefectsareusually
locatedoverareasoftypicalchildhoodtrauma,suchasbony
protuberancesofextremitiesorspinousprocesses

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 HISTORY

Epistaxisisafrequentpresentingsigninchildren
withhemostaticdisorders

Epistaxisisalsoacommoncomplaintamonghealthy
children,usuallytheresultoflocalaggravating
factors(drynasalmucosa,trauma,allergicrhinitis).

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 HISTORY

Menorrhagiaisalsoafrequentpresentingsignformildor

moderatebleedingdisorders(includingVWD,platelet

functiondisorders,andothercoagulopathies)andcanquickly

leadtosevereanaemiaanddecreasedqualityoflife.

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 HISTORY

Profusebleedingintosofttissuesorjointssuggests
deficiencyofacoagulationfactor(suchasfactorsVIII
orIX).
Umbilicalstumpbleedingistypicallyseenwith
factorXIIIdeficiency,butitmayalsooccurwith
deficienciesofprothrombin,factorX,andfibrinogen

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 HISTORY

Themaincategoriestobeconsideredshouldinclude
anatomicabnormalities,quantitativeandqualitative
plateletdefectsaffectingplateletplugformation
(primaryhemostasis),andquantitativeand
qualitativedefectsofclotpropagation(secondary
hemostasis).

Differentiationalsomustbemadebetweeninherited
andacquireddisorders.

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 HISTORY

Informationaboutthepatientspreviousresponseto
hemostaticchallenges(e.g.,surgicalprocedures,
invasivedentalwork,traumaticinjuries)isan
essentialpartoftheinitialevaluation
Familyhistoryisalsoakeycomponentinestablishing
boththelikelihoodofaninheritedbleedingdisorder
anditsspecificnature.

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Thethreephasesofcoagulationoccurondifferentcell
surfaces:initiationonthetissuefactorbearingcell;
amplificationontheplateletasitbecomesactivated;
andpropagationontheactivatedplateletsurface
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 HISTORY

Asickchildwithfever,shock,andmucocutaneous
purpuramayhavedisseminatedintravascular
coagulation(DIC)associatedwithbacteremia.
Hemophiliashouldbeconsideredinamaletoddler
whohasjuststartedcrawlingandexhibits
subcutaneousorjointbleeding,orwhobleedsafter
circumcision.
Agirlwhohashadseveremenorrhagiasince
menarchemayhaveVWD.

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 HISTORY

Awellappearingchildcoveredwithpetechiaelikely
hasimmunethrombocytopenia,butifthelesionsare
localizedtothebuttocks,ankles,andfeet,andthey
presentaspalpablebruises,HenochSchnlein
purpurashouldbeconsidered

Theprevalenceofbleedingdisordersinwomenwith
menorrhagiaisashighas20%,andmenorrhagiaisa
commoninitialsymptominwomenwithVWD
(approximately90%offemalepatients)
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 HISTORY

Medicaldisorderthatmayaffecthemostasis,hepatic
orrenaldisease,Malabsorptionsyndrome,or
EhlersDanlossyndrome(EDS)oranotherconnective
tissuedisorder.

Generally,earlyageofonsetcorrelateswithmore
severebleedingandmayindicateacongenitalcause.
Bleedingthatdevelopslaterinchildhoodmay
indicateeitheranacquiredproblemoramilder
congenitalbleedingdisorder
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 HISTORY

AnXlinkedrecessiveinheritancepattern(maternal
cousins,uncles,andgrandfather)suggestsa
diagnosisofhemophiliaAorB,
Autosomaldominantpatternwouldbemore
consistentwithVWDorhereditaryhaemorrhagic
telangiectasia.
Mostotherclinicallyrelevantclottingfactor
deficienciesareinheritedinanautosomalrecessive
manner

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 HISTORY

Anumberofdrugscancausethrombocytopenia
(e.g.,quinineorquinidine,rifampin,trimethoprim
sulfamethoxazole,carbamazepine,cimetidine,
ranitidine,valproicacid)

plateletdysfunction(nonsteroidalantiinflammatory
drugs[NSAIDs]suchasibuprofen[reversibleeffect]
andaspirin[irreversible]).

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 PHYSICALEXAMINATION

Signsofseverebleedingrelatedanaemiaor
intravascularvolumeloss,suchastachycardia(early
finding)orhypotension(latefinding).

observethepatternofbleedingstigmata

thepresenceofpetechiaeindicatesadefectin
primaryhemostasis(plateletnumberorfunctionor
vascularintegrity).

IAPUGTeachingslides201516 18
 PHYSICALEXAMINATION

Ecchymosesarepalpablepurplishlesionsinducedby
subcutaneousbleedingandusuallyindicateadefect
insecondaryhemostasis(clotpropagation),suchas
deficiencyofacoagulationfactor

Hemarthrosis,associatedwithseverecoagulation
factordeficiency

IAPUGTeachingslides201516 19
 PHYSICALEXAMINATION

Hepatomegalyandsplenicenlargementmaypoint

towardcoagulopathyassociatedwithsystemic

disorderssuchasleukaemiaorhepatocellular

disease.

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 LAB

Completebloodcountwithevaluationofplatelet
number,size,morphology,PT,APTT,andthrombin
time(TT)tohelpintheprocessofdifferential
diagnosis

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 LAB

IAPUGTeachingslides201516 22
IAPUGTeachingslides201516 23
 LAB

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 PLATELETS

Size:14m(youngerplateletsarelarger).
Distribution:onethirdinthespleen,twothirdsin
circulation
Averagelifespan:910days
Plateletscriticalcomponentforthefirstphaseof
hemostasis(formationoftheplateletplug),which
canhaltthelossofbloodfromvesselswhose
endothelialintegrityhasbeeninterrupted

IAPUGTeachingslides201516 25
 PLATELETS

Typicallyinvolvetheskinormucousmembranesand
includepetechiae,ecchymosis,epistaxis,
menorrhagia,andgastrointestinalhemorrhage.
Intracranialbleedingcanoccur,butitisinfrequent

Inheritedplateletdisorderscaninvolveaqualitative
and/orquantitativedefectandareoftenbroadly
classifiedaccordingtooneofthesetwocategories

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 BERNADSOULIERSYNDROME

BernardSouliersyndrome,aseverecongenital
plateletfunctiondisorder,iscausedbyabsenceor
severedeficiencyoftheVWFreceptor(GPIbcomplex)
ontheplateletmembrane.
Thrombocytopenia,withgiantplateletsand
markedlyprolongedbleedingtime(>20min)orPFA
100closuretime.
Plateletaggregationtestsshowabsentristocetin
inducedplateletaggregation,butnormal
aggregationtoallotheragonists.
IAPUGTeachingslides201516 27
 GLANZMANNTHROMBASTHENIA

Glanzmannthrombastheniaisacongenitaldisorder
associatedwithsevereplateletdysfunctionthat
yieldsprolongedbleedingtimeandanormalplatelet
count.
Plateletshavenormalsizeandmorphologicfeatures
ontheperipheralbloodsmear,andclosuretimesfor
PFA100orbleedingtimearemarkedlyabnormal

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 GLANZMANNTHROMBASTHENIA

Thisdisorderiscausedbydeficiencyofthe
plateletfibrinogenreceptorIIb3,themajor
integrincomplexontheplateletsurfacethat
undergoesconformationalchangesbyinsideout
signallingwhenplateletsareactivated

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 Densebodydeficiencyischaracterizedbyabsenceofthe
granulesthatcontainADP,ATP,Ca2+,andserotonin.This
disorderisdiagnosedbythefindingthatATPisnotreleased
onplateletaggregationstudiesandideallyischaracterizedby
electronmicroscopicstudies.

Grayplateletsyndromeiscausedbytheabsenceofplatelet
granules,resultinginplateletsthatappeargrayonWright
stainofperipheralblood.Inthisraresyndrome,aggregation
andreleaseareabsentwithmostagonistsotherthan
thrombinandristocetin.
IAPUGTeachingslides201516 30
 ForbothBernardSouliersyndromeandGlanzmannthrombasthenia,the
diagnosisisconfirmedbyflowcytometricanalysisofthepatient'splatelet
glycoproteins.

ForindividualswithBernardSouliersyndromeorGlanzmann
thrombasthenia,platelettransfusionsof1U/510kgcorrectsthedefectin
hemostasisandmaybelifesaving.

Desmopressin0.3g/kgIVmaybeusedformildtomoderatebleeding

episodes.

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 WISKOTTALDRICHSYNDROME

ThissyndromehasXlinkedinheritanceandhasthe
classicfeaturesofthrombocytopenia,eczema,
recurrentbacterialandviralinfections

WAShasabnormalTcellfunctionandapropensity
todevelopautoimmunedisorders

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 WISKOTTALDRICHSYNDROME

Recurrentpyogenicinfections,includingotitismedia,
pneumoniaandskininfections.Thereisalsolowered
resistancetononbacterialinfections,including
herpessimplexandPneumocystisjiroveci(formerly
carinii)pneumonia
Thrombocytopenia(plateletcount
10,000100,000/mm3);microthrombocytes;low
meanplateletvolume(MPV).

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 CAMT

CongenitalAmegakaryocyticThrombocytopenia
(CAMT)isabonemarrowfailuresyndromethat
presentswithisolatedthrombocytopeniainthe
neonatalperiod.Inheritanceisautosomalrecessive.
Themostcommonageatdiagnosisofthe
thrombocytopeniaiswithinthefirstmonth,because
ofpetechiaeandotherbleedingsymptoms.
ThediagnosisofCAMT,however,isnotusually
madeuntiltheinfantisseveralweeksormonthsold
whenthebonemarrowisexamined.
IAPUGTeachingslides201516 34
 TYPE2bVWD

Type2BvonWillebrandDisease.Type2BVWDisdue
toamutantVWFmoleculethatbindsspontaneously
toplateletsunderphysiologicshear.
Thisresultsinclearanceofthehighestmolecular
weightmultimersandusuallymild
thrombocytopenia

IAPUGTeachingslides201516 35
 ITP

Immunethrombocytopeniaisadisordercausedby
antiplateletantibodieswhichleadtoanaccelerated
destructionofplateletsandaninhibitionoftheproductionof
platelets.
ITPisthemostcommoncauseofthrombocytopeniain
children.
Peakoccurrenceisbetween2and5yearsofage.
Inmostchildrenthediseaseisselflimited,withresolutionin
80%ofpatientswithin612monthsfromdiagnosis

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 ITP

Antibodymediateddestruction:
Mostoftheidentifiedautoantibodiesaredirected
againstGPIIbGPIIIa,GPIbGPIXandGPIaIia
Impairedmegakaryopoiesis
Antibodyandcellularcytotoxicityandimmunecell
derivedcytokineshavebeenimplicatedinimpairment
ofmegakaryocytes

IAPUGTeachingslides201516 37
 CLINICALFEATURES
Typicallypatientsareotherwisewellandpresent
withpetechiae,purpuraandnopalpableecchymosis
13weeksafteraviralinfection.
Itmayalsooccurafterrubella,rubeola,chickenpox
orlivevirusvaccination.
Occasionallypatientsmaypresentwithmucosal
bleeding(hematuria,hematochezia,
Menometrorrhagia,orepistaxis).
Mostoften,bleedingsymptomsaremild,butrarely
patientsmaydevelopseverebleedingincluding
intracranialhemorrhage
IAPUGTeachingslides201516 38
 AmericanSocietyofHematology(ASH)
DEFINITIONS

PrimaryITPwasdefinedbytheIWGasaplateletcountless
than100X109/L

TheIWGalsodefinesITPasnewlydiagnosed(diagnosisto3
months),persistent(3to12monthsfromdiagnosis),or
chronic(lastingformorethan12months).

Completeresponse(CR):Aplateletcount100X109/L
measuredon2occasions7daysapartandtheabsenceof
bleeding.
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 ASHDEFINITIONS

Response(R):Aplateletcount30X109/Landagreaterthan
2foldincreaseinplateletcountfrombaselinemeasuredon2
occasions7daysapartandtheabsenceofbleeding

Noresponse(NR):Aplateletcount30X109/Loralessthan
2foldincreaseinplateletcountfrombaselineorthe
presenceofbleeding.Plateletcountmustbemeasuredon2
occasionsmorethanadayapart.

IAPUGTeachingslides201516 40
Bloodsmearandbonemarrowaspiratefromachildwho
hadITPshowinglargeplatelets(bloodsmear[left])and
increasednumbersofmegakaryocytes,manyofwhich
appearimmature(bonemarrowaspirate

IAPUGTeachingslides201516 41
 TREATMENT

Notherapyotherthaneducationandcounsellingofthe
familyandpatientforpatients

AsingledoseofIVIG[intravenousimmunoglobulin](0.81.0
g/kg)12days

Prednisone.Dosesofprednisoneof14mg/kg/24hrappear
toinduceamorerapidriseinplateletcountthaninuntreated
patientswithITP

IAPUGTeachingslides201516 42
 TREATMENT

IntravenousantiDtherapy.ForRhpositivepatients,IVantiD
atadoseof5075g/kgcausesariseinplateletcountto

>20109/Lin8090%ofpatientswithin4872hr

TheroleofsplenectomyinITPshouldbereservedfor1of2
circumstances.

Theolderchild(4yr)withsevereITPthathaslasted>1yr
(chronicITP)andwhosesymptomsarenoteasilycontrolled
withtherapyisacandidateforsplenectomy
IAPUGTeachingslides201516 43
 ASHGUIDELINES

Bonemarrowexaminationisunnecessaryinchildren

andadolescentswiththetypicalfeaturesofITP

(grade1B).

Bonemarrowexaminationisnotnecessaryin

childrenwhofailIVIgtherapy(grade1B).

IAPUGTeachingslides201516 44
ThankYou

IAPUGTeachingslides201516 45