Thrombocytopenia in Infants and Children Deborah M ... · Pediatrics in Review Vol.32 No.4 April 2011 135 ... hematology thrombocytopenia Pediatrics in Review Vol.32 No.4 April 2011

DOI: 10.1542/pir.32-4-1352011;32;135Pediatrics in Review

Deborah M. ConsoliniThrombocytopenia in Infants and Children

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Thrombocytopenia in Infants and ChildrenDeborah M. Consolini,

MD*

Author Disclosure

Dr Consolini has

disclosed no financial

relationships relevant

to this article. This

commentary does

contain a discussion

of an unapproved/

investigative use of a

commercial

product/device.

Objectives After completing this article, readers should be able to:

1. Explain the relationship between platelet count and bleeding risk.2. State the two basic underlying pathologic mechanisms that may lead to clinically

significant thrombocytopenia.3. Describe the typical presentation and natural history of immune (idiopathic) thrombo-

cytopenic purpura (ITP) in children.4. List the features of the complete blood count and peripheral blood smear that suggest

a serious disorder associated with decreased platelet production.5. Discuss the treatment modalities that have been proven to be effective in raising the

platelet count to a safe level in children who have ITP and are experiencing significantbleeding manifestations.

IntroductionPlatelets are essential for maintaining the integrity of the vascular endothelium andcontrolling hemorrhage from small-vessel injury through the formation of platelet plugs(primary hemostasis). More extensive injury and involvement of larger blood vesselsrequires, in addition to platelets, the participation of the coagulation system to provide afirm, stable, fibrin clot (secondary hemostasis). Thrombocytopenia, defined as a plateletcount of less than 150�103/�L (150�109/L), is the most common cause of defectiveprimary hemostasis that can lead to significant bleeding in children.

Thrombocytopenia should be suspected when a child presents with a history of easybruising or bleeding, particularly mucosal or cutaneous bleeding. However, the mostcommon office presentation of a patient who has isolated thrombocytopenia is the

unexpected discovery of a low platelet count when a com-plete blood count (CBC) is obtained for unrelated reasons.

Thrombocytopenia can be caused by one of two mecha-nisms: decreased production of platelets or increased de-struction or removal of platelets from the circulation. Man-agement of thrombocytopenia should be guided by anunderstanding of its cause and clinical course. The principalmanagement goal in all patients who have thrombocytopeniais to maintain a safe platelet count to prevent significantbleeding. What constitutes a safe platelet count in a specificpatient varies, depending on the cause of the thrombocyto-penia and consideration of all other aspects of hemostasis, aswell as the patient’s expected level of activity.

Platelet Count and Bleeding RiskPlatelets are nonnucleated, cellular fragments produced bythe megakaryocytes of the bone marrow. As the megakaryo-cyte matures, the cytoplasm fragments, and large numbers ofplatelets are released into the circulation. Once released, thelife span of platelets is about 7 to 10 days, after which they areremoved from the circulation by cells of the monocyte-

*Assistant Professor of Pediatrics, Thomas Jefferson University, Philadelphia, PA; Diagnostic Referral Division, A.I. duPontHospital for Children, Wilmington, DE.

Abbreviations

CBC: complete blood countDIC: disseminated intravascular coagulationHIV: human immunodeficiency virusHUS: hemolytic-uremic syndromeICH: intracranial hemorrhageIg: immunoglobulinIGIV: immune globulin intravenousITP: immune thrombocytopenic purpuraKMS: Kasabach-Merritt syndromeMPV: mean platelet volumeNAIT: neonatal alloimmune thrombocytopeniaNEC: necrotizing enterocolitisPBS: peripheral blood smearSLE: systemic lupus erythematosusTTP: thrombotic thrombocytopenic purpuraWAS: Wiscott-Aldrich syndrome

Article hematology

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macrophage system. In disorders characterized by in-creased platelet destruction and shortened platelet lifespan, a healthy marrow may increase platelet productionover the basal rate by about tenfold.

Circulating platelets perform many critical hemostaticfunctions. When small blood vessels are transected, plate-lets accumulate at the site of injury, forming a hemostaticplug. Platelet adhesion is initiated by contact with ex-travascular components, such as collagen, and facilitatedby the presence and binding of von Willebrand factor.Secretion of mediators of hemostasis (eg, thromboxane,adenosine 5� diphosphate, serotonin, and histamine)cause firm aggregation via fibrinogen binding and in-crease local vasoconstriction. Platelets also are necessaryfor normal clot retraction. Bleeding risk increases with alow platelet count.

The normal platelet count ranges from 150 to450�103/�L (150 to 450�109/L). The risk of bleed-ing does not increase until the platelet count falls signif-icantly below 100�103/�L (100�109/L) (Fig. 1). (1)A platelet count greater than 50�103/�L (50�109/L)is adequate for hemostasis in most circumstances, andpatients who have mild thrombocytopenia will likelynever be recognized unless a platelet count is obtainedfor other reasons. Patients who have moderate throm-bocytopenia, with platelet counts between 30 and50�103/�L (30 and 50�109/L) are rarely symptom-atic (ie, easy bruising or bleeding), even with significanttrauma. Patients who have persistent platelet countsbetween 10 and 30�103/�L (10 and 30�109/L) are

often asymptomatic with normaleveryday activities but may be atrisk for excessive bleeding withsignificant trauma. Spontaneousbleeding typically does not occurunless platelet counts are less than10�103/�L (10�109/L). Suchpatients commonly have petechiaeand spontaneous bruising, but eventhey may be entirely asymptomatic.In most cases, it appears that theplatelet count must be less than5�103/�L (5�109/L) to causecritical spontaneous bleeding (eg,atraumatic intracranial hemorrhage[ICH]). (1)

Younger circulating platelets arelarger and more hemostaticallyactive. Thus, patients who havedestructive thrombocytopenias ac-companied by a brisk production

and release of younger platelets have less severe bleedingsymptoms than patients who have a similar degree ofthrombocytopenia due to impaired platelet production,resulting in an older circulating population of platelets.

Causes of ThrombocytopeniaThe system used most often to categorize the differentcauses of thrombocytopenia is based on the underlyingpathologic mechanism leading to the thrombocytopenia,that is, either increased destruction or decreased produc-tion of platelets (Table 1).

Increased DestructionDisorders involving increased destruction or removal ofplatelets from the circulation typically result in the ap-pearance of enlarged platelets on the peripheral bloodsmear (PBS), indicating that the bone marrow is pro-ducing new platelets to compensate for the increaseddestruction. In this setting, examination of the bonemarrow generally shows normal or increased numbers ofmegakaryocytes. The destructive mechanisms resultingin thrombocytopenia are:

● Immune-mediated destruction● Platelet activation and consumption● Mechanical platelet destruction● Platelet sequestration and trapping

IMMUNE-MEDIATED DESTRUCTION. The most com-mon cause of thrombocytopenia due to increased de-

Figure 1. Relationship between major bleeding and platelet count. Adapted from SlichterSJ. Relationship between platelet count and bleeding risk in thrombocytopenic patients.Transfus Med Rev. 2004;18:153–167.

hematology thrombocytopenia

136 Pediatrics in Review Vol.32 No.4 April 2011



struction of platelets in infants and children is animmune-mediated process. Autoantibodies, drug-dependent antibodies, or alloantibodies may mediateplatelet destruction through interaction with plateletmembrane antigens, leading to increased platelet clear-ance from the circulation.

Primary ITP is an acquired immune-mediated disor-der characterized by isolated thrombocytopenia in theabsence of any obvious initiating or underlying cause.(2)(3) Formerly, the abbreviation ITP stood for idio-pathic thrombocytopenic purpura. The new terminologyreflects the current understanding of the immune-

mediated nature of the disease and the absence or mini-mal signs of bleeding in most cases. The platelet countnow used to define cases of ITP is less than 100�103/�L(100�109/L). (2) The term secondary ITP refers toimmune-mediated thrombocytopenias that are due to anunderlying disease or to drug exposure. (2)(3) The dis-tinction between primary and secondary ITP is clinicallyrelevant both in regard to prognosis and treatment.

ITP is the most common immune-mediated throm-bocytopenia in children, with an annual incidence ofsymptomatic cases estimated to be between 3 and 8 casesper 100,000 children. Pediatric patients who developITP usually present between the ages of 2 and 10 years,with a peak incidence at 2 to 5 years. There does notappear to be a significant sex bias in childhood ITP.(4)(5)

The typical case of symptomatic childhood ITP ischaracterized by the sudden appearance of bruising ormucocutaneous bleeding in an otherwise healthy child,often after a preceding viral illness. An increased risk ofITP is also associated with measles, mumps, rubella im-munization, which accounts for perhaps 50% of all ITPcases during the second year after birth. This form of ITPtends to be transient and rarely is the bleeding severe.

The history should reveal no systemic symptoms suchas fever, weight loss, or bone pain. Other than muco-cutaneous bleeding, patients should appear well. Nolymphadenopathy or hepatosplenomegaly should bepresent. If one or more of these findings are present,another diagnosis should be strongly considered. Other-wise, the diagnosis of ITP can be made based on twocriteria: 1) isolated thrombocytopenia with otherwisenormal blood counts and PBS and 2) no clinically appar-ent associated conditions that may cause thrombocyto-penia.

The severity of bleeding symptoms in childhood ITPis proportionate to the degree of thrombocytopenia.Serious bleeding requiring transfusion is uncommon.The presenting platelet count is usually less than20�103/�L (20�109/L). This value probably is due topatients who have higher platelet counts, which are muchless likely to lead to bleeding, never coming to medicalattention. Children who have ITP and platelet countsgreater than 30�103/�L (30�109/L) usually have fewor no symptoms and require no treatment other thanrestriction of activity and avoidance of medications thathave antiplatelet or anticoagulant activity. For thosewhose platelet counts are below 30�103/�L (30�109/L), treatment recommendations are based on the pres-ence and severity of associated bleeding symptoms or therisk thereof. (4)(6)

Table 1. Causes ofThrombocytopeniaIncreased Platelet Destruction

● Immune-mediated–Immune thrombocytopenic purpura–Neonatal alloimmune thrombocytopenia–Neonatal autoimmune thrombocytopenia–Autoimmune diseases–Drug-induced

● Platelet activation/consumption–Disseminated intravascular coagulation–Hemolytic-uremic syndrome–Thrombotic thrombocytopenic purpura–Kasabach-Merritt syndrome–Necrotizing enterocolitis–Thrombosis

● Mechanical platelet destruction● Platelet sequestration

–Chronic liver disease–Type 2B and platelet-type von Willebrand disease–Malaria

Decreased Platelet Production

● Infection● Cyanotic congenital heart disease● Bone marrow failure or infiltrate

–Acute lymphoblastic leukemia and othermalignancies

–Acquired aplastic anemia–Fanconi pancytopenia

● Nutritional deficiencies● Genetically impaired thrombopoiesis

–Thrombocytopenia with absent radii syndrome–Congenital amegakaryocytic thrombocytopenia–Wiskott-Aldrich syndrome–X-linked thrombocytopenia with thalassemia–Giant platelet disorders–Bernard-Soulier syndrome–May-Hegglin/Fechtner/Epstein and Sebastiansyndromes




ITP is now classified by duration into newly diag-nosed, persistent (3- to 12-month duration), andchronic (�12-month duration). (2)(3) Whereas ITP inadults typically has an insidious onset and follows achronic course, ITP in children is usually short-lived,with about two thirds of patients making full and sus-tained recoveries within 6 months of presentation, withor without treatment. (2)(3) Children who have persis-tent or chronic ITP or who manifest any atypical featuresshould be referred to or discussed with a hematologistexperienced in the assessment and treatment of childrenwho have ITP.

Neonatal alloimmune thrombocytopenia (NAIT) isan uncommon syndrome whose estimated incidence inthe general population is 1 in 1,000 to 5,000 births. Thecondition is manifested by an isolated, transient, butpotentially severe thrombocytopenia in the neonate dueto platelet destruction by maternal alloantibodies. NAIToccurs when fetal platelets contain an antigen inheritedfrom the father that the mother lacks. Fetal platelets thatcross the placenta into the maternal circulation triggerthe production of maternal immunoglobulin (Ig) Gantiplatelet antibodies against the foreign antigen. Theseantibodies recross the placenta into the fetal circulationand destroy the body’s platelets, resulting in fetal andneonatal thrombocytopenia (analogous to hemolytic dis-ease of the newborn). In contrast to Rh sensitization,NAIT often develops in the first pregnancy of an at-riskcouple. The most serious complication of NAIT is ICH,which occurs in approximately 10% to 20% of affectednewborns, with up to 50% of these events occurring inutero. (7) The mother of a newborn who has NAIT isasymptomatic, although she may have a history of previ-ously affected pregnancies. Affected newborns typicallypresent with signs consistent with severe thrombocyto-penia, including petechiae, bruising, and bleeding, butare otherwise healthy. Platelet counts are often less than10�103/�L (10�109/L). The platelet count typicallyfalls in the first few days after birth, but then rises over thenext 1 to 4 weeks as the alloantibody concentrationdeclines. In families who have an affected infant, the rateof recurrence is as high as 75% to 90%, and thrombocy-topenia in the second affected child is always as or moresevere than in the first. (7)

Neonatal autoimmune thrombocytopenia also canoccur. This disorder is mediated by maternal antibodiesthat react with both maternal and infant platelets. Thispathologic mechanism occurs in maternal autoimmunedisorders, including ITP and systemic lupus erythemato-sus (SLE). The diagnosis usually is apparent from themother’s medical history and maternal thrombocytope-

nia. Mothers of infants who manifest unexplained neo-natal thrombocytopenia should be investigated for thepresence of an autoimmune disorder because neonatalthrombocytopenia can sometimes be the presenting signof maternal disease. Clinical signs are consistent withisolated thrombocytopenia, as in NAIT.

The risk of severe thrombocytopenia and ICH isgreater in alloimmune than in autoimmune neonatalthrombocytopenia. Ninety percent of infants born tomothers who have ITP have safe (�50�103/�L[50�109/L]) or normal platelet counts. (8) The risk forsevere thrombocytopenia in the infant generally corre-lates with the severity of ITP in the mother. Neonatalthrombocytopenia may be predicted if the mother hashad a splenectomy for treatment of chronic refractoryITP, the mother’s platelet count has been less that50�103/�L (50�109/L) at some time during the preg-nancy, or an older sibling has had neonatal thrombocy-topenia. (8) Platelet counts of infants born to motherswho have ITP often decrease sharply during the firstseveral days after birth. The nadir typically occurs at 2 to5 days of age, and infants should be monitored closelyduring this time. (8)

Autoimmune diseases such as SLE can present inchildhood with isolated immune-mediated thrombocy-topenia, and the true diagnosis may not be apparent for aprolonged period of time. Autoimmune diseases occurmore commonly in older children and have an insidiousonset of symptoms and persistent thrombocytopeniabeyond 6 months from the time of presentation. In-frequently, other autoimmune-mediated cytopeniaspresent coincidentally with thrombocytopenia. In partic-ular, Evans syndrome is characterized by a Coombs(direct antiglobulin test)-positive hemolytic anemia inassociation with immune-mediated thrombocytopenia.Antibody-mediated thrombocytopenia also occurs withantiphospholipid antibody syndrome and autoimmunelymphoproliferative syndrome.

Drug-induced thrombocytopenia is a rare cause ofthrombocytopenia in children. Medications begunwithin the past month are more likely to be the cause ofthe thrombocytopenia than medications that have beentaken for longer periods of time. Drug-induced throm-bocytopenia is typically caused by drug-dependent anti-bodies formed against a new antigen on the plateletsurface that is created by drug binding to a plateletsurface protein. Heparin-induced thrombocytopenia,which can be associated with severe thrombosis, is due tothe formation of antibodies against the heparin-plateletfactor 4 complex. The platelet count in heparin-inducedthrombocytopenia is usually only moderately decreased.





Although this condition is more commonly seen inadults, heparin-induced thrombocytopenia has beendescribed in children. Other drugs commonly used inpediatrics that can cause thrombocytopenia include car-bamazepine, phenytoin, valproic acid, trimethoprim/sulfamethoxazole, and vancomycin. Support for the di-agnosis of drug-induced thrombocytopenia is providedby resolution of the thrombocytopenia within approxi-mately 1 week of withdrawal of the offending drug.

PLATELET ACTIVATION AND CONSUMPTION. In pa-tients who experience disseminated intravascular co-agulation (DIC) and the microangiopathic disordershemolytic-uremic syndrome (HUS) and thromboticthrombocytopenic purpura (TTP), thrombocytopeniaoccurs because of systemic platelet activation, aggrega-tion, and consumption (Table 2). More localized plateletactivationandconsumptioncontributestothethrombocy-topenia seen in Kasabach-Merritt syndrome (KMS), ne-crotizing enterocolitis (NEC), and thrombosis in infantsand neonates. In infants who have KMS, thrombocyto-penia results from shortened platelet survival caused bysequestration of platelets and coagulation activa-tion in large vascular malformations of the trunk, extrem-ities, or abdominal viscera. Cutaneous vascular lesionsare noted at birth in approximately 50% of patients.Detection of visceral lesions requires imaging studies. Allpatients have severe thrombocytopenia, hypofibrinogen-emia, elevated fibrin degradation products, and fragmen-tation of red blood cells on PBS.

NEC is a syndrome of gastrointestinal necrosis thatoccurs in 2% to 10% of infants whose birthweights areless than 1,500 g. Thrombocytopenia is a frequent find-ing and can result in significant bleeding. In the earlystages of NEC, declining platelet counts correlate withthe presence of necrotic bowel and worsening disease.The primary mechanism of thrombocytopenia appearsto be platelet destruction, although the destruction isnot caused by laboratory-detectable DIC in most cases.Thrombosis in infants and neonates is often accompa-nied by thrombocytopenia. A thromboembolic disordershould be considered if the thrombocytopenia cannot beexplained by other conditions.

MECHANICAL PLATELET DESTRUCTION. The use of ex-tracorporeal therapies, such as extracorporeal membraneoxygenation, cardiopulmonary bypass, hemodialysis, andapheresis, is associated with mechanical destruction ofplatelets, which may result in thrombocytopenia. Ex-change transfusion also may reduce platelet number byloss in the exchange effluent. Severe ongoing hemor-

rhage requiring rapid and repeated red blood cell trans-fusions may lead to thrombocytopenia due to a “washout” phenomenon.

PLATELET SEQUESTRATION AND TRAPPING. Aboutone third of the platelet mass is normally sequestered inthe spleen at any given time. A greater proportion ofplatelets are sequestered in patients who experience hy-persplenism, reducing the number of circulating plateletsand leading to thrombocytopenia. The survival of plate-lets in persons who have hypersplenism is normal or nearnormal. It is the pooling and unavailability of platelets“trapped” in the spleen that is the problem. Leukopeniaor anemia also may accompany a low platelet countcaused by hypersplenism. Conditions in this categoryinclude:

● Chronic liver disease with portal hypertension andcongestive splenomegaly. Occasionally, isolated throm-bocytopenia may be the initial manifestation of thistype of chronic liver disease. The platelet count istypically in the range of 50 to 100�103/�L (50 to100�103/L) and usually does not represent a clinicallyimportant problem.

● Type 2B and platelet-type von Willebrand disease.Thrombocytopenia in this disorder is caused by in-creased removal of platelets from the circulation. In-creased binding between larger von Willebrand factormultimers and platelets leads to the formation of smallplatelet aggregates that are cleared from the circula-tion, resulting in a lower platelet count.

● Malaria with hypersplenism. This diagnosis should beconsidered in any child who has fever, splenomegaly,thrombocytopenia, and a history of recent travel to anendemic area.

Decreased ProductionImpaired platelet production may be due to loss of bonemarrow space from infiltration, suppression or failure ofcellular elements, or a defect in megakaryocyte develop-ment and differentiation. In this setting, examination ofthe bone marrow generally shows decreases in the num-ber of megakaryocytes. Causes of marrow dysfunctioninclude:

● Infection● Cyanotic heart disease● Bone marrow failure or infiltration● Nutritional deficiencies● Genetic defects




Tab

le2.

Diso

rder

sof

Syst

emic

Plat

elet

Acti

vati

onan

dCo

nsum

ptio

nPa

thop

hysio

logy

Clin

ical

Feat

ures

Diag

nosis

Trea

tmen

tPr

ogno

sis

Diss

emin

ated

intr

avas

cula

rco

agul

atio

n(D

IC)

Path

olog

icac

tivat

ion

ofco

agul

atio

nm

echa

nism

s,re

sulti

ngin

exte

nsiv

em

icro

vasc

ular

thro

mbo

sisle

adin

gto

ische

mia

and

end-

orga

nda

mag

e.

Cons

umpt

ion

ofpl

atel

ets

and

coag

ulat

ion

fact

ors

and

activ

atio

nof

fibrin

olys

isre

sult

inhe

mor

rhag

e.

Com

plic

atio

nof

unde

rlyin

gill

ness

essu

chas

seps

is,as

phyx

ia,m

econ

ium

aspi

ratio

n,se

vere

resp

irato

rydi

stre

sssy

ndro

me,

exte

nsiv

etr

aum

a.

Sym

ptom

sin

clud

ebl

eedi

ng,

hypo

tens

ion,

incr

ease

dva

scul

arpe

rmea

bilit

y,an

dsh

ock.

yTh

rom

bocy

tope

nia

yFr

agm

ente

dRB

Csy

Prol

onge

dPT

,aPT

Ty

Decr

ease

dpl

asm

afib

rinog

eny

Incr

ease

dFD

Ps

Only

effe

ctiv

eth

erap

yis

reve

rsal

ofun

derly

ing

caus

e.

Tem

poriz

ing

mea

sure

sin

clud

e:•

Plat

elet

tran

sfus

ions

for

blee

ding

,sev

ere

thro

mbo

cyto

peni

a•

FFP

tore

plen

ishco

agul

atio

nan

dan

tithr

ombo

ticfa

ctor

s

Varie

s,de

pend

ing

onth

eun

derly

ing

diso

rder

and

the

exte

ntof

the

intr

avas

cula

rth

rom

bosis

,but

rega

rdle

ssof

caus

eis

ofte

ngr

im,w

ith10

%to

50%

mor

talit

y.

Hem

olyt

ic-u

rem

icsy

ndro

me

(HUS

)M

ost

case

spr

eced

edby

episo

deof

bloo

dydi

arrh

eadu

eto

vero

toxi

n-pr

oduc

ing

Esch

eric

hia

coli

O157

H7.

Vero

toxi

nen

ters

bloo

dstr

eam

,at

tach

esto

glom

erul

aren

doth

eliu

m,a

ndin

activ

ates

the

met

allo

prot

ease

ADAM

TS13

,re

spon

sible

for

clea

ving

very

larg

em

ultim

ers

ofvW

F.Un

clea

ved

vWF

initi

ates

plat

elet

aggr

egat

ion

and

activ

atio

n,re

sulti

ngin

netw

ork

ofm

icro

thro

mbi

inki

dney

sth

atle

adto

frag

men

tatio

nof

RBCs

,co

nsum

ptio

nof

plat

elet

s,an

dtis

sue

ische

mia

.

Less

com

mon

form

with

out

diar

rhea

poss

ibly

due

tofa

ctor

Hde

ficie

ncy

with

unco

ntro

lled

com

plem

ent

activ

atio

nan

dth

rom

bosis

afte

rm

inor

endo

thel

iali

njur

y.

Seen

pred

omin

antly

inch

ildre

n.Us

ually

prec

eded

byep

isode

ofbl

oody

diar

rhea

.

Onse

tof

illne

ssch

arac

teriz

edby

pallo

ran

dol

igur

iaw

ithth

rom

bocy

tope

nia

and

labo

rato

ryev

iden

ceof

mic

roan

giop

athi

che

mol

ytic

anem

iaan

dAR

F.

yTh

rom

bocy

tope

nia

yFr

agm

ente

dRB

Csy

Incr

ease

dBU

N,c

reat

inin

ey

Nor

mal

PT,a

PTT

yN

orm

alpl

asm

afib

rinog

eny

Nor

mal

FDPs

Supp

ortiv

eca

re.

Dial

ysis,

asne

eded

,unt

ilev

iden

ceof

reco

verin

gre

nal

func

tion.

Antib

iotic

trea

tmen

tno

tre

com

men

ded

beca

use

itm

ayst

imul

ate

furt

her

vero

toxi

npr

oduc

tion.

Plat

elet

tran

sfus

ions

may

wor

sen

outc

ome.

Ifdi

agno

stic

unce

rtai

nty

betw

een

HUS

and

TTP

beca

use

ofne

urol

ogic

orot

her

nonr

enal

invo

lvem

ent,

plas

ma

exch

ange

reco

mm

ende

d.

Mor

talit

yra

teis

5%to

10%

.Mos

tsu

rviv

ors

reco

ver

with

out

maj

orco

nseq

uenc

es.S

mal

lpr

opor

tion

ofpa

tient

sde

velo

psch

roni

cre

nal

insu

ffici

ency

.

Thro

mbo

ticth

rom

bocy

tope

nic

purp

ura

(TTP

)M

ost

com

mon

lyas

soci

ated

with

inhi

bitio

nof

ADAM

TS13

byau

toan

tibod

ies.

Asin

HUS,

with

out

prop

ercl

eava

geof

vWF,

spon

tane

ous

coag

ulat

ion

occu

rs.

InTT

P,a

netw

ork

ofm

icro

thro

mbi

inm

ultip

leor

gan

syst

ems

resu

ltsin

clin

ical

and

labo

rato

ryfin

ding

s.Ra

rer

form

calle

dUp

shaw

-Sch

ulm

ansy

ndro

me

isa

gene

tical

lyin

herit

eddy

sfun

ctio

nof

ADAM

TS13

.

•Th

rom

bocy

tope

nia

•M

icro

angi

opat

hic

hem

olyt

ican

emia

•AR

F•

Neu

rolo

gic

sym

ptom

s•

Feve

r

ARF

and

neur

olog

icsy

mpt

oms

may

not

bepr

esen

tin

itial

ly.F

ever

unco

mm

on.O

nly

thro

mbo

cyto

peni

aan

dm

icro

angi

opat

hic

hem

olyt

ican

emia

with

out

othe

rap

pare

ntca

use

requ

ired

tosu

spec

tdi

agno

sis.

yTh

rom

bocy

tope

nia

yFr

agm

ente

dRB

Csy

Elev

ated

LDH

yIn

crea

sed

BUN

,cre

atin

ine

yN

orm

alPT

,aPT

Ty

Nor

mal

plas

ma

fibrin

ogen

yN

orm

alFD

Psy

Decr

ease

d(<

5%of

norm

al)

ADAM

TS13

activ

ityy

Dete

ctab

lein

hibi

tors

ofAD

AMTS

13

Daily

plas

ma

exch

ange

usin

gFF

Pre

duce

san

ti-AD

AMTS

13an

tibod

ies

and

repl

enish

esco

ncen

trat

ions

ofth

een

zym

e.M

aybe

need

edfo

r1

to8

wee

ksbe

fore

labo

rato

ryva

lues

norm

alize

.

Upsh

aw-S

chul

man

synd

rom

epa

tient

sre

ceiv

eFF

Pev

ery

2to

3w

eeks

tom

aint

ain

adeq

uate

conc

entr

atio

nsof

func

tioni

ngen

zym

e.

Mor

talit

yra

te�

95%

for

untr

eate

dca

ses

but

10%

to20

%fo

rpa

tient

str

eate

dea

rlyw

ithpl

asm

aex

chan

ge.

Appr

oxim

atel

y30

%of

patie

nts

expe

rienc

ea

rela

pse

with

in10

year

sof

the

first

atta

ck.

aPT

T�

activ

ated

part

ialt

hrom

bopl

astin

time,

AR

F�ac

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rena

lfai

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bloo

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INFECTION. Thrombocytopenia due to infections notassociated with evidence of DIC is usually caused bybone marrow suppression. In some cases, increased de-struction due to an infection-induced immune-mediatedprocess or splenomegaly and reticuloendothelial hyper-activity may compound the problem of bone marrowsuppression. The most common infectious agents asso-ciated with thrombocytopenia due to bone marrow sup-pression are Epstein-Barr virus, cytomegalovirus, parvo-virus, varicella virus, and rickettsiae. In most cases, thethrombocytopenia is transient, with recovery within aperiod of weeks. Thrombocytopenia is a common find-ing in patients who are infected with the human immu-nodeficiency virus (HIV), in whom both platelet destruc-tion and impaired production appear to play roles indecreasing the platelet count.

CYANOTIC HEART DISEASE. Cyanotic congenital heartdisease is associated with thrombocytopenia. The cause isunclear, but the mechanism appears to involve decreasedproduction of megakaryoctes.

BONE MARROW FAILURE OR INFILTRATION. Throm-bocytopenia associated with anemia and leukopenia (ie,pancytopenia) suggests general bone marrow dysfunc-tion or infiltration. Serious disorders such as leukemia orother malignancy, hemophagocytic lymphohistiocytosis,acquired aplastic anemia, myelodysplasia, and inheritedbone marrow failure syndromes such as Fanconi pancy-topenia syndrome and dyskeratosis congenita can presentwith pancytopenia. General bone marrow dysfunctioncan also be caused by exposure to chemotherapeuticagents or radiation.

Acute lymphoblastic leukemia is the most commonchildhood leukemia. Affected children usually have otherclinical and laboratory findings besides thrombocytope-nia. These manifestations include systemic symptomssuch as fever, bone pain, and weight loss as well ashepatosplenomegaly, lymphadenopathy, leukocytosis,and anemia.

Acquired aplastic anemia is a rare disorder caused byprofound, almost complete bone marrow failure. Specificsymptoms associated with acquired aplastic anemia varybut can include fever, fatigue, dizziness, weakness, head-aches, and episodes of excessive bleeding. Pancytopeniais often seen on presentation. Based on the response ofapproximately 50% of patients to immunosuppressivemedications, including antithymocyte globulin, cyclo-sporine, high-dose corticosteroids, and cyclophosph-amide, most cases are now believed to be due to an

immune-mediated destruction of hematopoietic stemcells.

Fanconi pancytopenia syndrome is a rare autosomalrecessive disorder. The mean age at diagnosis of thepancytopenia is approximately 6 to 9 years, but thecondition may be recognized earlier by characteristiccongenital malformations that are present in 60% to 70%of affected patients. The most common malformationsare hypopigmented macules, cafe-au-lait macules, abnor-malities of the thumbs, microcephaly, and urogenitalabnormalities. Short stature of prenatal onset may also beseen.

NUTRITIONAL DEFICIENCIES. Folate, vitamin B12, andiron deficiencies have been associated with thrombocy-topenia. Folate and vitamin B12 deficiencies impair bonemarrow production, usually resulting in pancytopenia.Iron deficiency, which can cause either thrombocytosisor thrombocytopenia, appears to impair a late stage ofthrombopoiesis. Thrombocytosis and iron deficiencymay be a response to gastrointestinal blood loss.

GENETIC CAUSES OF IMPAIRED THROMBOPOIESIS. Alarge number of rare inherited diseases present withreduced platelet count, and many involve impaired plate-let function as well. These conditions arise from geneticdefects of the megakaryocyte lineage that result in im-paired thrombopoiesis. The consideration of congenitalthrombocytopenia should be greater in patients whohave a prolonged history of asymptomatic abnormalplatelet counts or a family history of thrombocytopenia.Some patients born with congenital thrombocytopeniaare followed for many years with the presumptive diag-nosis of ITP until another family member is discoveredto have a low platelet count. Table 3 outlines the geneticcauses of impaired thrombopoiesis.

Clinical ManifestationsChildren who have thrombocytopenia may be asymp-tomatic or symptomatic. In asymptomatic patients,thrombocytopenia is often detected unexpectedly on aCBC obtained for another clinical issue. Symptomaticpatients generally present with mucosal or cutaneousbleeding.

Mucosal bleeding usually manifests as epistaxis, gin-gival bleeding or extensive oral mucous membranebleeding (“wet purpura”), hematuria, or in postpubertalfemales, excessive menstrual bleeding. The presence of“wet purpura” is widely perceived as a risk factor forpotentially life-threatening hemorrhage.

Cutaneous bleeding usually appears as petechiae or




Tab

le3.

Gene

tic

Caus

esof

Impa

ired

Thro

mbo

poie

sis

Diag

nosi

sIn

herit

ance

Caus

eCl

inic

alFe

atur

esLa

bora

tory

Feat

ures

Prog

nosi

sTr

eatm

ent

Thro

mbo

cyto

peni

aw

ithab

sent

radi

isyn

drom

eVa

riabl

ein

herit

ance

Uncl

ear

gene

ticca

use.

Poss

ible

defe

ctof

meg

akar

yocy

tem

atur

atio

n.Do

esno

tin

volv

eei

ther

thro

mbo

poie

tinor

thro

mbo

poie

tinre

cept

or.

●Se

vere

thro

mbo

cyto

peni

a●

Bila

tera

labs

ent

radi

i●

Nor

mal

thum

bs●

Oth

ersk

elet

al,g

enito

urin

ary,

hear

tan

omal

ies

●Ab

sent

orm

arke

dly

decr

ease

dm

egak

aryo

cyte

s●

Nor

mal

eryt

hroi

dan

dm

yelo

idm

atur

atio

n

Mor

talit

ysi

gnifi

cant

inin

fanc

ydu

eto

intr

acra

nial

hem

orrh

age.

Ifpa

tient

surv

ives

,th

rom

bocy

tope

nia

ofte

nim

prov

esov

erne

xtse

vera

lyea

rs.

●Pl

atel

ettr

ansf

usio

ns

Cong

enita

lam

egak

aryo

cytic

thro

mbo

cyto

peni

aAu

toso

mal

rece

ssiv

eM

utat

ions

inth

rom

bopo

ietin

rece

ptor

gene

,lea

ding

toab

sent

ordy

sfun

ctio

nal

thro

mbo

poie

tinre

cept

ors.

●Se

vere

but

isol

ated

thro

mbo

cyto

peni

a●

Abse

ntor

mar

kedl

yde

crea

sed

meg

akar

yocy

tes

●N

orm

aler

ythr

oid

and

mye

loid

mat

urat

ion

Oft

enpr

ogre

sses

topa

ncyt

open

iaan

dle

ukem

ictr

ansf

orm

atio

n

●Pl

atel

ettr

ansf

usio

ns●

Bone

mar

row

tran

spla

ntat

ion

Wis

kott

-Ald

rich

synd

rom

eX-

linke

dre

cess

ive

diso

rder

Abno

rmal

gene

onpr

oxim

alar

mof

Xch

rom

osom

een

code

sre

gula

tory

prot

ein

ofly

mph

ocyt

ean

dpl

atel

etfu

nctio

n.

●At

opic

derm

atiti

s●

Thro

mbo

cyto

peni

cpu

rpur

a●

Incr

ease

dsu

scep

tibili

tyto

infe

ctio

ns

●Sm

all(

3to

5fL

)de

fect

ive

plat

elet

s●

Nor

mal

-app

earin

gm

egak

aryo

cyte

s

Surv

ival

beyo

ndte

ens

rare

.In

fect

ions

orbl

eedi

ngar

em

ajor

caus

esof

deat

h.12

%in

cide

nce

offa

tal

mal

igna

ncy.

Sple

nect

omy

may

impr

ove

plat

elet

coun

tbu

tof

ten

com

plic

ated

byov

erw

helm

ing

seps

is/

deat

hGi

ant

plat

elet

diso

rder

s●

Bern

ard-

Soul

ier

synd

rom

e

Auto

som

alre

cess

ive

Dysf

unct

ion/

abse

nce

ofpl

atel

etre

cept

orfo

rvo

nW

illeb

rand

fact

or(G

PIb

-IX

-V)

●Ea

sybr

uisi

ngan

dse

vere

hem

orrh

age

with

trau

ma/

surg

ery

●M

acro

thro

mbo

cyto

peni

a,se

vere

plat

elet

dysf

unct

ion

Blee

ding

tend

ency

lifel

ong

For

both

Bern

ard-

Soul

ier,

MYH

9RD:

Desm

opre

ssin

acet

ate

may

shor

ten

blee

ding

time.

Plat

elet

tran

sfus

ions

for

surg

ery/

seve

rebl

eedi

ng.

Bern

ard-

Soul

ier

patie

nts

may

deve

lop

antip

late

let

antib

odie

sbe

caus

eof

GPIb

-IX-

Von

tran

sfus

edpl

atel

ets.

●M

YH9-

rela

ted

dise

ase

(MYH

9RD)

Auto

som

aldo

min

ant

Non

mus

cle

myo

sin

heav

ych

ain

gene

(MYH

9)m

utat

ions

●Bl

eedi

ng,n

ephr

itis,

hear

ing

loss

,cat

arac

ts.E

pste

in,

Fech

tner

,Seb

astia

nsy

ndro

me

orM

ay-H

eggl

inan

omal

ypr

evio

usly

diag

nose

dba

sed

onsp

ecifi

ccl

inic

alfin

ding

sat

pres

enta

tion

but

now

rega

rded

ason

edi

sord

er.

●M

acro

thro

mbo

cyto

peni

a,le

ukoc

yte

incl

usio

ns,

hem

atur

ia,p

rote

inur

ia

Prog

ress

ive

high

-fre

quen

cyse

nsor

ineu

ralh

earin

glo

ss,

glom

erul

onep

hriti

san

dca

tara

cts

may

deve

lop

anyt

ime

betw

een

infa

ncy

and

adul

thoo

d.





superficial ecchymoses. Patients who have thrombocyto-penia may also have persistent, profuse bleeding fromsuperficial cuts. Petechiae, the pinhead-sized, red, flat,discrete lesions caused by extravasation of red cells fromskin capillaries and often occurring in crops in dependentareas, are highly characteristic of decreased platelet num-ber or function. Petechiae are nontender and do notblanch under pressure. They are asymptomatic and notpalpable and should be distinguished from small telangi-ectasias and vasculitic (palpable) purpura. Purpura de-scribes purplish discolorations of the skin due to thepresence of confluent petechiae. Ecchymoses are non-tender areas of bleeding into the skin that are typicallysmall, multiple, and superficial and can develop withoutnoticeable trauma. Ecchymoses often have a variety ofcolors due to the presence of extravasated blood (red orpurple) and the ongoing breakdown of heme pigment inthe extravasated blood by skin macrophages (green, yel-low, or brown).

This pattern of bleeding differs from that of patientswho have disorders of coagulation factors, such as hemo-philia. Patients who have thrombocytopenia tend to haveless deep bleeding into muscles or joints, more bleedingafter minor cuts, less delayed bleeding, and less postsur-gical bleeding. In addition, patients who have coagula-tion factor disorders tend not to have petechiae. Al-though rare, bleeding into the central nervous system isthe most common cause of death due to thrombocyto-penia. When such bleeding occurs, it is often preceded bya history of head trauma.

EvaluationA thorough history and physical examination and judi-cious use of laboratory testing can lead to the appropriatediagnosis in most patients (Fig. 2). Patients should bequestioned about past and current bleeding symptoms,including bruising with little or no trauma, nosebleeds,blood in the urine or stool, gum bleeding, bleeding withsurgical or dental procedures, or excessive menstrualbleeding. Duration and onset of the bleeding symptomsmay help determine whether the cause is acquired orcongenital. If thrombocytopenia is due to an acquiredcause, the onset of symptoms may be linked to a specifictrigger (eg, infection). Congenital thrombocytopeniashould be considered in patients who have a prolongedhistory of asymptomatic abnormal platelet counts or afamily history of thrombocytopenia.

In children who have suspected or known thrombo-cytopenia, the skin, gingivae, and oral cavity should beexamined carefully for evidence of bleeding. In hospital-ized patients, careful examination for bleeding should be

performed at the site of indwelling catheters, drains, andincisions or areas of previous trauma. Table 4 lists the“red flags” in the history and physical examination ofchildren who have thrombocytopenia that should lead toconsideration of diagnoses other than ITP.

Laboratory EvaluationThe laboratory evaluation of thrombocytopenia beginswith a CBC and evaluation of the PBS. Although a dyingskill for most general practitioners, the ability to assessthe PBS accurately is invaluable in the evaluation ofchildren who have thrombocytopenia or other hemato-logic abnormalities. Consultation with a hematopatholo-gist or experienced laboratory technologist may be use-ful.

The CBC should be examined closely for the plateletcount and mean platelet volume (MPV) as well as forevidence of any other cytopenias (anemia or leukopenia).A platelet count that does not make sense clinicallyshould be confirmed before undertaking extensive eval-uation to be sure that thrombocytopenia exists and thefinding is not due to artifact or laboratory error. Spuriousthrombocytopenia can be caused by improper collectionor inadequate anticoagulation of the blood sample, re-sulting in platelet clumps that are counted as leukocytesby automated cell counters. Once thrombocytopeniahas been confirmed, an MPV that is significantly higherthan normal suggests one of the macrothrombocyto-penia syndromes. A mildly elevated MPV is consistentwith a destructive cause. A low MPV is typically seen inpatients who have Wiscott-Aldrich syndrome (WAS)gene mutations.

The PBS should be examined to estimate the plateletnumber (1 platelet/high power field�platelet count of�10�103/�L [10�109/L]), determine the plateletmorphology and the presence or absence of plateletclumping, and assess whether there are associated whiteand red blood cell changes. Large platelets suggest eitheran ongoing platelet destructive process leading to theproduction of younger and larger platelets or the pres-ence of a congenital macrothrombocytopenia syndrome.Small platelets in the appropriate clinical setting suggestWAS. The presence of schistocytes suggests a micro-angiopathic process such as DIC, HUS, or TTP. Sphero-cytes suggest autoimmune hemolytic anemia coupledwith immune-mediated thrombocytopenia (Evans syn-drome).

Other tests may be useful in determining the cause ofthe thrombocytopenia but are generally performed basedon suggestive findings from the initial history and phys-ical examination and laboratory testing. A positive direct




Coombs test suggests an autoimmune process in a pa-tient who has evidence of hemolysis as well as spherocyteson the PBS. For patients who have persistant or chronicITP, antinuclear antibody, serum immunoglobulins(IgG, IgA, IgM), and antiphospholipid antibodiesshould be considered. Fibrin degradation products andfibrinogen measurements are useful to diagnose intravas-cular coagulation.

If the PBS results are consistent with a microangio-pathic process, additional tests should be considered,including serum lactate dehydrogenase and creatinine toassess for HUS or TTP. HIV testing should be consid-ered because thrombocytopenia may be the initial diseasemanifestation in as many as 10% of patients who haveHIV infection. If clinical suspicion or local prevalence ishigh, tests to identify hepatitis C viral infection or Heli-cobacter pylori infection should also be considered.

Screening tests for inherited disorders associated withthrombocytopenia should be considered in patients whoexperience chronic thrombocytopenia, especially in thepresence of short stature or other congenital anomalies.

Platelet antibodies can be detected by a variety ofassays. Although many of these assays have high sensitiv-ity, they lack specificity and are not indicated or per-formed routinely to confirm the diagnosis of acute ITP inchildren.

A bone marrow examination is not necessary in mostcases of isolated unexplained thrombocytopenia in chil-dren. In general, a bone marrow examination is indicatedwhen clinical signs or symptoms suggest either marrowinfiltration or failure. These findings include pancytope-nia; the presence of blasts on the PBS; and the presenceof systemic symptoms such as fever, fatigue, weight loss,or bone pain. A bone marrow examination also is indi-

Figure 2. Diagnostic algorithm for thrombocytopenia. CAMT�congenital amegakaryocytic thrombocytopenia, DIC�disseminatedintravascular coagulation, HUS�hemolytic-uremic syndrome, TAR�thrombocytopenia with absent radii syndrome, TTP�thromboticthrombocytopenic purpura, WAS�Wiscott-Aldrich syndrome.





cated for unexplained, chronic, stable thrombocytope-nia, even when the presumed diagnosis is ITP, or if thesubsequent clinical course is inconsistent with the naturalhistory of ITP because of the development of new clinicalsigns or symptoms or laboratory abnormalities.

TreatmentManagement of thrombocytopenia in an individual pa-tient should be guided by an understanding of its causeand predicted clinical course. Correction of the causemay not be possible (eg, congenital thrombocytopenias)or may not be necessary (eg, mild-to-moderate ITP).The principal management goal in all patients who havethrombocytopenia is to maintain a safe platelet count toprevent significant bleeding, not to achieve a normalplatelet count. What constitutes a safe platelet count in aparticular patient varies, depending on the cause of thethrombocytopenia and consideration of all other aspectsof hemostasis. For patients who have significant bleedingsymptoms, treatment is essential. Asymptomatic or min-imally symptomatic thrombocytopenia may be treated ifthe thrombocytopenia is severe or the perceived risk ofbleeding is great.

Activity RestrictionsWhen moderate-to-severe thrombocytopenia is recog-nized, implementing reasonable precautions to minimizebleeding risk is recommended. These steps includetrauma precautions (eg, avoidance of contact sports anduse of a helmet while cycling) and avoidance of medica-tions that have antiplatelet or anticoagulant activity (in-cluding aspirin-containing preparations, ibuprofen, andother nonsteroidal anti-inflammatory drugs).

Invasive ProceduresA platelet count greater than 50�103/�L (50�109/L)provides safety for most invasive procedures. If the risksof potentially serious bleeding are believed to be severe,a platelet count of greater than 100�103/�L (100�109/L) is often required by surgeons or anesthesiolo-gists. For common minor procedures, such as toothextractions, a platelet count of 30 to 50�103/�L(50�109/L) often is sufficient. (1) For patients whohave lower platelet counts, some measure to increase theplatelet count immediately before the procedure may berequired. A short course of corticosteroids (prednisone2 mg/kg per day for 1 week) or a single dose of immuneglobulin intravenous (IGIV) (1 g/kg) is often sufficientto increase the platelet count acutely for proceduralhemostasis. Platelet transfusions can be used in urgentsituations. Although platelet survival in the circulation of

patients who have destructive thrombocytopenias maynot be normal, platelet transfusion nearly always providesprompt, satisfactory hemostasis, even if only for a shortduration.

Emergency Management of Critical BleedingPatients who have severe thrombocytopenia and criticalbleeding require immediate transfusion of platelets re-gardless of the cause of the thrombocytopenia. ICH isthe most serious consequence of severe thrombocyto-penia. Early diagnostic imaging should be consideredfor patients who have severe thrombocytopenia andneurologic signs or symptoms to identify ICH. Forpatients who have unstable or progressive ICH, emer-gency craniotomy may be necessary. For patients whohave ITP with life-threatening bleeding, in addition toplatelets, adjunctive treatment with high doses of corti-costeroid (intravenous methylprednisolone 30 mg/kg

Table 4. Red Flags Suggesting aDiagnosis Other Than ImmuneThrombocytopenic PurpuraHistory

● Fever● Bone pain● Weight loss● Fatigue● Recent history of infections or vaccinations● Past medical history of diseases associated with

thrombocytopenia (eg, autoimmune disorders,cirrhosis)

● Dietary history suggestive of iron, vitamin B12, orfolate deficiency

● Exposure to medications known to be associatedwith thrombocytopenia

● Travel history to an endemic area for malaria

Physical Examination

● Lymphadenopathy● Splenomegaly● Joint swelling● Short stature● Limb defects, including radial agenesis and thumb

abnormalities● Cataracts● Sensorineural hearing loss● Oral leukoplakia● Dystrophic nails● Eczema in male patient● Frequent infections● Superficial hemangiomas




Tab

le5.

Init

ialT

reat

men

tfo

rN

ewly

Diag

nose

dIm

mun

eTh

rom

bocy

tope

nic

Purp

ura

(ITP)

Wit

hSi

gnifi

cant

Blee

ding

orRi

skof

Blee

ding

Trea

tmen

tM

echa

nism

ofAc

tion

Resp

onse

Rate

Toxi

citie

sCo

mm

ents

Cort

icos

tero

ids

Dosi

ngva

ries

from

pred

niso

ne2

mg/

kgpe

rda

yor

ally

for

2to

4w

eeks

tohi

gh-d

ose

met

hylp

redn

isol

one

30m

g/kg

per

day

(max

imum

,1g)

intr

aven

ousl

yfo

r3

to7

days

●Re

duce

san

tibod

ypr

oduc

tion

●Re

duce

sre

ticul

oend

othe

lial

syst

emph

agoc

ytos

isof

antib

ody-

coat

edpl

atel

ets

●Im

prov

esva

scul

arin

tegr

ity●

Impr

oves

plat

elet

prod

uctio

n

Upto

75%

achi

eve

plat

elet

resp

onse

,dep

endi

ngon

dose

;res

pons

eto

ther

apy

usua

llyw

ithin

2to

7da

ys

●Be

havi

oral

chan

ges

●Sl

eep

dist

urba

nce

●In

crea

sed

appe

tite

●W

eigh

tga

in●

Gast

ritis

/gas

troi

ntes

tinal

hem

orrh

age

●Im

mun

osup

pres

sion

●Po

orlin

ear

grow

th

●N

ocu

rativ

ebe

nefit

know

n●

Oft

en,a

drop

inpl

atel

etco

unt

afte

rst

eroi

dsdi

scon

tinue

d●

Repe

ated

cour

ses

may

bene

cess

ary

ifsi

gnifi

cant

blee

ding

sym

ptom

spe

rsis

tor

recu

rIm

mun

eGl

obul

inIn

trav

enou

s(IG

IV)

Sing

ledo

se1

g/kg

Unkn

own

and

likel

ym

ultif

acto

rial.

Theo

ries

incl

ude:

●Re

ticul

oend

othe

lials

yste

mbl

ocka

de/in

hibi

tion

●Au

toan

tibod

yne

utra

lizat

ion

byan

ti-id

ioty

pean

tibod

ies

●In

crea

sed

auto

antib

ody

clea

ranc

edu

eto

com

petit

ive

inhi

bitio

nof

imm

unog

lobu

linFc

rece

ptor

>80

%ac

hiev

epl

atel

etre

spon

se;r

espo

nse

toth

erap

yus

ually

with

in24

hour

s

●N

ause

a/vo

miti

ng●

Seve

rehe

adac

he●

Feve

r●

Chill

s●

Mor

epr

onou

nced

inol

der

patie

nts

●N

ocu

rativ

ebe

nefit

know

n●

30%

have

sign

ifica

ntdr

opin

plat

elet

coun

tin

2to

6w

eeks

●IG

IVap

pear

sto

impr

ove

plat

elet

coun

tsm

ore

relia

bly

than

cort

icos

tero

ids

orno

trea

tmen

t.So

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up to 1 g/day for 3 days) and a single dose of IGIV(1 g/kg) is also appropriate. Emergency splenectomymay be considered in cases of refractory ITP accompa-nied by life-threatening hemorrhage.

Thrombocytopenia Associated With OtherCytopenias

Patients who have pancytopenia with systemic symptomsor significant findings on examination should be evalu-ated carefully in a timely manner because they are atincreased risk for a serious disorder that may requireurgent intervention. Consultation with a pediatric hema-tologist should be strongly considered. Treatment of theidentified underlying primary disorder guides subse-quent management. For such patients, maintenance of asafe platelet count may be only a small part of the overalltreatment plan.

Isolated ThrombocytopeniaThe most likely diagnosis in an otherwise healthy childwho has isolated thrombocytopenia is ITP. Most patientsdo not have serious bleeding (including those whoseplatelet counts are �10�103/�L [10�109/L]). ICH isextremely rare, with an incidence of 0.1% to 0.5%. Al-though treatments for childhood ITP may reduce theseverity and duration of the initial thrombocytopenicepisode and presumably the risk of bleeding, they do notappear to affect the eventual recovery rate. Up to twothirds of children who have ITP recover within 6 monthsof presentation with or without treatment. (3)(5)

Most experts agree that pharmacologic interventionis not generally needed for children who have mild-to-moderate thrombocytopenia (platelet counts �30�103/�L] 30�109/L]) because they are unlikely to haveserious bleeding. Exceptions to this policy include chil-dren who have concomitant or preexisting conditionsthat increase their risk for severe bleeding and childrenundergoing procedures likely to include blood loss. (6)

For patients whose platelet counts are less than30�103/�L (30�109/L), treatment recommendationsare based on the presence and severity of associatedbleeding or the risk thereof. Although there is no definedmeans to predict which children who have ITP will sufferfrom an ICH, retinal hemorrhages and extensive muco-sal bleeding or “wet purpura” have been reported toprecede and possibly predict spontaneous ICH. (4)Thus, any individual who has ITP and actual or obviouspotential for significant bleeding requires immediatetreatment, regardless of the platelet count.

When therapy is indicated, the primary treatmentoptions for the newly diagnosed patient are corticoste-

roids, IGIV, and anti-Rho(D) immune globulin (Table5). Several studies have shown that the duration ofsymptomatic thrombocytopenia is shortened by any ofthese three interventions compared with no treatment.All ITP therapies are temporizing interventions intendedfor rapid reversal of a real or perceived risk for significanthemorrhage. They do not need to be continued untilnormal platelet counts are reached. Therapy is targetedto increase the platelet count above a threshold (usually�20�103/�L [20�109/L]) that stops bleeding oreliminates the risk of serious bleeding. (6) Platelet trans-fusions are indicated in patients who have ITP only inthe setting of life-threatening bleeding, such as ICH.Because of accelerated platelet destruction in ITP, plate-let transfusions result in a relatively limited rise in theplatelet count of very short duration (measured in hoursor even minutes) that may be adequate for the immediatehemostasis required in the setting of ICH but otherwiseis of no benefit.

Almost all children who develop ITP are treated in theambulatory setting. Patients who require pharmacologicintervention with IGIV or high-dose intravenous corti-costeroids are usually hospitalized for an average of 1 to3 days. Platelet counts are monitored once or twiceweekly, depending on the clinical situation and severityof the thrombocytopenia. When recovery of plateletcounts is detected, the interval between platelet countassessment may be lengthened. Monitoring should con-tinue until the platelet count has returned to normal andis stable.

Approximately 20% to 30% of children who presentwith ITP eventually develop chronic ITP, defined aspersistent thrombocytopenia beyond 12 months fromthe time of presentation. Patients who have chronic ITPare usually clinically indistinguishable from those whohave acute ITP at presentation. Children younger than10 years of age are more likely to have remissions thanolder patients. Children whose bleeding manifestationslast more than 14 days are substantially more likely todevelop chronic ITP.

All children who have persistent (3 to 12 months) orchronic (�12 months) ITP should have their cases re-viewed and managed by a pediatric hematologist. Indi-viduals who have chronic ITP should undergo evaluationthat includes bone marrow examination to exclude othercauses of thrombocytopenia. In chronic ITP, plateletcounts tend to range between 20 and 75�103/�L(20 and 75�109/L); consequently, many patients re-quire no or only intermittent treatment for episodes ofsignificant bleeding or increased risk of bleeding.

A small percentage of pediatric patients who have ITP





and significant hemorrhagic symptoms demonstrate re-sistance to both corticosteroids and IGIV. Managementof such so-called refractory ITP is difficult (Table 6).

Pulse intermittent high-dose corticosteroids and sple-nectomy have been the mainstays of treatment in thesesituations, although not without significant risks. Newertreatment modalities that may be useful include ritux-imab, a chimeric anti-CD20 monoclonal antibody, andthe thrombopoietin receptor agonists romiplostim andeltrombopag, although studies of these agents in chil-dren are limited (9)(10)(11) and not approved by theUnited States Food and Drug Administration for chil-dren younger than 18 years. The recent use of thrombo-poietin receptor agonists reflects a new paradigm in thetreatment of ITP, with the focus not on reducing plateletconsumption through immune modulation or suppres-sion but on increasing platelet production.

References1. Slichter SJ. Relationship between platelet count and bleedingrisk in thrombocytopenic patients. Transfus Med Rev. 2004;18:153–1672. Rodeghiero F, Stasi R, Gemsheimer T, et al. Standardization ofterminology, definitions and outcome criteria in immune thrombo-cytopenic purpura of adults and children: report from an interna-tional working group. Blood. 2009;113:2386–23933. Provan D, Stasi R, Newland A, et al. International consensusreport on the investigation and management of primary immunethrombocytopenia. Blood. 2010;115:168–1864. Medeiros D, Buchanan GR. Current controversies in the man-agement of idiopathic thrombocytopenic purpura during child-hood. Pediatr Clin North Am. 1996;43:757–7725. Kuhne T, Buchanan GR, Zimmerman S, et al. A prospectivecomparative study of 2540 infants and children with newly diag-nosed idiopathic thrombocytopenic purpura (ITP) from the In-tercontinental Childhood ITP Study Group. J Pediatr. 2003;143:605–6086. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombo-cytopenic purpura: a practice guideline developed by explicitmethods for the American Society of Hematology. Blood. 1996;88:3–407. Bussel JB, Zabusky MR, Berkowitz RL, et al. Fetal alloimmunethrombocytopenia. N Engl J Med. 1997;337:22–268. Payne SD, Resnik R, Moore TR, et al. Maternal characteristicsand risk of severe neonatal thrombocytopenia and intracranial hem-orrhage in pregnancies complicated by autoimmune thrombocyto-penia. Am J Obstet Gynecol. 1997;177:149–1559. Wang J, Wiley JM, Luddy R, et al. Chronic immune thrombo-cytopenic purpura in children: assessment of rituximab treatment.J Pediatr. 2005;146:217–22110. Bennett CM, Rogers ZR, Kinnamon DD, et al. Prospectivephase I/II study of rituximab in childhood and adolescentchronic immune thrombocytopenic purpura. Blood. 2006;107:2639–264211. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy oflong-term treatment with romiplostim in thrombocytopenic pa-tients with chronic ITP. Blood. 2009;113:2161–2171

Summary• Thrombocytopenia should be suspected in any child

presenting with a history of easy bruising orbleeding or petechiae, but it also may present as anincidental finding in an asymptomatic individual.

• Thrombocytopenia may be caused by either increaseddestruction or removal of platelets from thecirculation or decreased production of platelets.

• Destructive mechanisms resulting inthrombocytopenia include immune-mediateddestruction, platelet activation and consumption,mechanical platelet destruction, and plateletsequestration or trapping.

• Impaired platelet production may be due to bonemarrow infiltration, suppression, or failure or defectsin megakaryocyte development and differentiation.

• A thorough history and physical examination andjudicious use of laboratory testing can lead to theappropriate diagnosis in most patients who havethrombocytopenia.

• Childhood ITP generally presents with the suddenappearance of bruising, bleeding, or petechiae in anotherwise healthy child.

• The diagnosis of ITP can be made using two criteria:1) isolated thrombocytopenia with otherwise normalblood counts and peripheral blood smear and 2) noclinically apparent associated conditions that maycause thrombocytopenia.

• Further evaluation, including bone marrowassessment, should be considered in patients whohave atypical clinical or laboratory features atpresentation; thrombocytopenia lasting more than 6months; or a subsequent clinical course that isinconsistent with the natural history of ITP,including failure to respond to usually effectivetherapies.

• Management of thrombocytopenia should be guidedby an understanding of its cause and clinical course,with the principal goal in all patients being tomaintain a safe platelet count to prevent significantbleeding.

• For childhood ITP, pharmacologic intervention,including corticosteroids, IGIV, and anti-Rho(D)immune globulin, has been shown to raise theplatelet count more quickly than no therapy and isrecommended for children who have or at risk forsevere or life-threatening bleeding, based on strongevidence.

• ITP in children usually is short-lived, with at leasttwo thirds of patients making a full and sustainedrecovery within 6 months of presentation, with orwithout treatment.




PIR QuizQuiz also available online at http://pedsinreview.aappublications.org.

1. A 4-year-old boy is brought to the office with a 3-week history of bruising. He has had no othercomplaints. He has mild bruising but no petechiae and no mucosal bleeding. His physical examinationfindings are otherwise normal. Laboratory results include a white blood cell count of 8.4�103/�L(8.4�109/L), hemoglobin of 13.4 g/dL (134 g/L), and platelet count of 31�103/�L (31�109/L). The mostappropriate management is:

A. High-dose intravenous corticosteroids.B. Intravenous anti-D.C. Intravenous gamma globulin.D. Observation.E. Oral corticosteroids.

2. A 4-year-old girl presents with a 5-week history of bruising but is otherwise well. On physical examination,the only abnormal finding is increased bruising and scattered petechiae. Her platelet count is 29�103/�L(29�109/L), hemoglobin is 9.5 g/dL (95 g/L), and white blood cell count is 2.1�103/�L (2.1�109/L). Themost appropriate next step is to:

A. Administer antibiotics.B. Observe the child.C. Obtain antiplatelet antibodies.D. Obtain Ebstein-Barr virus titers.E. Perform a bone marrow aspiration.

3. An 18-month-old girl has a blood count performed at a health supervision visit. The child is well and herphysical examination findings are normal. The laboratory calls because the platelet count is 1�103/�L(1�109/L). The hemoglobin is 13.5 g/dL (135 g/L), white blood cell count is 7.6�103/�L (7.6�109/L), andabsolute neutrophil count is 3.9x103/�L (3.9�109/L). The most appropriate next step is to:

A. Measure immunoglobulins, antinuclear antibody, and antiphospholipid antibodies.B. Measure prothrombin and partial thromboplastin times.C. Perform a bone marrow aspiration.D. Refer to a pediatric hematologist.E. Repeat the platelet count.

4. A 6-year-old boy who has known chronic immune thrombocytopenic purpura is involved in a motor vehicleaccident and arrives in the emergency department unresponsive. Emergency computed tomography scan ofthe head reveals a large subdural hematoma. The child’s blood type is A-negative. The platelet count is1�103/�L (1�109/L). You administer a platelet transfusion and high doses of intravenousmethylprednisolone and begin intravenous gamma globulin. During the emergency craniotomy, it is difficultto control the bleeding. The most appropriate next therapy is:

A. Anti-D immune globulin.B. Cyclophosphamide.C. Emergency splenectomy.D. Plasmapheresis.E. Rituximab (anti-CD 20 monoclonal antibody).





CorrectionsThe caption for Figure 2 in the article entitled “Focus on Diagnosis: Urine Electrolytes” inthe February issue of the journal (Pediatr Rev. 2011;32:65–68) is incorrect. The correctcaption should read, “A graphic illustration of a positive urine anion gap, with the numberof unmeasured anions exceeding the number of unmeasured cations. When this situationoccurs in the context of metabolic acidosis, it is consistent with renal tubular acidosis,indicating an impaired ability to excrete protons in the urine as ammonium.” We regret theerror.

The caption for Figure 1 in the article entitled “Sacral Dimples” in the March issue ofthe journal (Pediatr Rev. 2011;32:109–114) is incorrect. The correct caption should read,“Solitary dimple whose location is greater than 2.5 cm above the anus indicated the needfor further evaluation. . . .” We regret the error.

5. A 7-year-old girl presents with a 3-day history of bruising and an episode of epistaxis lasting 30 minutes.On physical examination, the only abnormalities are scleral icterus, widespread bruising, and cutaneous aswell as mucosal petechiae. Laboratory results include a platelet count of 3�103/�L (3�109/L), hemoglobinof 7.8 g/dL (78 g/L), white blood cell count of 12.9�103/�L (12.9�109/L), absolute neutrophil count of8.8�103/�L (8.8�109/L), and mean corpuscular volume of 86 fL. Urinalysis is negative for red blood cells.The most appropriate next study is:

A. Antiplatelet antibodies.B. Bone marrow aspirate.C. Direct antiglobulin (Coombs) test.D. Flow cytometry on peripheral blood.E. Serum blood urea nitrogen and creatinine assessment.




DOI: 10.1542/pir.32-4-1352011;32;135Pediatrics in Review

Deborah M. ConsoliniThrombocytopenia in Infants and Children

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