Thrombocytopenia: in Infants and Children

Article hematology
Thrombocytopenia in Infants and Children

Deborah M. Consolini,
Objectives After completing this article, readers should be able to:
MD*
1. Explain the relationship between platelet count and bleeding risk.
2. State the two basic underlying pathologic mechanisms that may lead to clinically
Author Disclosure significant thrombocytopenia.
Dr Consolini has 3. Describe the typical presentation and natural history of immune (idiopathic) thrombo-
disclosed no financial cytopenic purpura (ITP) in children.
relationships relevant 4. List the features of the complete blood count and peripheral blood smear that suggest
to this article. This a serious disorder associated with decreased platelet production.
commentary does 5. Discuss the treatment modalities that have been proven to be effective in raising the
contain a discussion platelet count to a safe level in children who have ITP and are experiencing significant
of an unapproved/ bleeding manifestations.
investigative use of a
commercial
product/device.
Introduction
Platelets are essential for maintaining the integrity of the vascular endothelium and
controlling hemorrhage from small-vessel injury through the formation of platelet plugs
(primary hemostasis). More extensive injury and involvement of larger blood vessels
requires, in addition to platelets, the participation of the coagulation system to provide a
firm, stable, fibrin clot (secondary hemostasis). Thrombocytopenia, defined as a platelet
count of less than 150!103/!L (150!109/L), is the most common cause of defective
primary hemostasis that can lead to significant bleeding in children.
Thrombocytopenia should be suspected when a child presents with a history of easy
bruising or bleeding, particularly mucosal or cutaneous bleeding. However, the most
common 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-
Abbreviations
nisms: decreased production of platelets or increased de-
CBC: complete blood count struction or removal of platelets from the circulation. Man-
DIC: disseminated intravascular coagulation agement of thrombocytopenia should be guided by an
HIV: human immunodeficiency virus understanding of its cause and clinical course. The principal
HUS: hemolytic-uremic syndrome management goal in all patients who have thrombocytopenia
ICH: intracranial hemorrhage is to maintain a safe platelet count to prevent significant
Ig: immunoglobulin bleeding. What constitutes a safe platelet count in a specific
IGIV: immune globulin intravenous patient varies, depending on the cause of the thrombocyto-
ITP: immune thrombocytopenic purpura penia and consideration of all other aspects of hemostasis, as
KMS: Kasabach-Merritt syndrome well as the patient’s expected level of activity.
MPV: mean platelet volume
NAIT: neonatal alloimmune thrombocytopenia Platelet Count and Bleeding Risk
NEC: necrotizing enterocolitis Platelets are nonnucleated, cellular fragments produced by
PBS: peripheral blood smear the megakaryocytes of the bone marrow. As the megakaryo-
SLE: systemic lupus erythematosus cyte matures, the cytoplasm fragments, and large numbers of
TTP: thrombotic thrombocytopenic purpura platelets are released into the circulation. Once released, the
WAS: Wiscott-Aldrich syndrome life span of platelets is about 7 to 10 days, after which they are
removed from the circulation by cells of the monocyte-
*Assistant Professor of Pediatrics, Thomas Jefferson University, Philadelphia, PA; Diagnostic Referral Division, A.I. duPont
Hospital for Children, Wilmington, DE.
Pediatrics in Review Vol.32 No.4 April 2011 135

Downloaded from http://pedsinreview.aappublications.org/ at Instituto Nacional de Pediatria on January 22, 2015
hematology thrombocytopenia
often asymptomatic with normal

everyday activities but may be at
risk for excessive bleeding with
significant trauma. Spontaneous
bleeding typically does not occur
unless platelet counts are less than
10!103/!L (10!109/L). Such
patients commonly have petechiae
and spontaneous bruising, but even
they may be entirely asymptomatic.
In most cases, it appears that the
platelet count must be less than
5!103/!L (5!109/L) to cause
critical spontaneous bleeding (eg,
atraumatic intracranial hemorrhage
[ICH]). (1)
Figure 1. Relationship between major bleeding and platelet count. Adapted from Slichter Younger circulating platelets are
SJ. Relationship between platelet count and bleeding risk in thrombocytopenic patients. larger and more hemostatically
Transfus Med Rev. 2004;18:153–167. active. Thus, patients who have
destructive thrombocytopenias ac-
companied by a brisk production
macrophage system. In disorders characterized by in- and release of younger platelets have less severe bleeding
creased platelet destruction and shortened platelet life symptoms than patients who have a similar degree of
span, a healthy marrow may increase platelet production thrombocytopenia due to impaired platelet production,
over the basal rate by about tenfold. resulting in an older circulating population of platelets.
Circulating platelets perform many critical hemostatic
functions. When small blood vessels are transected, plate- Causes of Thrombocytopenia
lets accumulate at the site of injury, forming a hemostatic The system used most often to categorize the different
plug. Platelet adhesion is initiated by contact with ex- causes of thrombocytopenia is based on the underlying
travascular components, such as collagen, and facilitated pathologic mechanism leading to the thrombocytopenia,
by the presence and binding of von Willebrand factor. that is, either increased destruction or decreased produc-
Secretion of mediators of hemostasis (eg, thromboxane, tion of platelets (Table 1).
adenosine 5" diphosphate, serotonin, and histamine)
cause firm aggregation via fibrinogen binding and in- Increased Destruction
crease local vasoconstriction. Platelets also are necessary Disorders involving increased destruction or removal of
for normal clot retraction. Bleeding risk increases with a platelets from the circulation typically result in the ap-
low platelet count. pearance of enlarged platelets on the peripheral blood
The normal platelet count ranges from 150 to smear (PBS), indicating that the bone marrow is pro-
450!103/!L (150 to 450!109/L). The risk of bleed- ducing new platelets to compensate for the increased
ing does not increase until the platelet count falls signif- destruction. In this setting, examination of the bone
icantly below 100!103/!L (100!109/L) (Fig. 1). (1) marrow generally shows normal or increased numbers of
A platelet count greater than 50!103/!L (50!109/L) megakaryocytes. The destructive mechanisms resulting
is adequate for hemostasis in most circumstances, and in thrombocytopenia are:
patients who have mild thrombocytopenia will likely
never be recognized unless a platelet count is obtained ● Immune-mediated destruction
for other reasons. Patients who have moderate throm- ● Platelet activation and consumption
bocytopenia, with platelet counts between 30 and ● Mechanical platelet destruction
50!103/!L (30 and 50!109/L) are rarely symptom- ● Platelet sequestration and trapping
atic (ie, easy bruising or bleeding), even with significant

trauma. Patients who have persistent platelet counts IMMUNE-MEDIATED DESTRUCTION. The most com-
between 10 and 30!103/!L (10 and 30!109/L) are mon cause of thrombocytopenia due to increased de-
136 Pediatrics in Review Vol.32 No.4 April 2011

mediated nature of the disease and the absence or mini-

Causes of
Table 1. mal signs of bleeding in most cases. The platelet count
now used to define cases of ITP is less than 100!103/!L
Thrombocytopenia (100!109/L). (2) The term secondary ITP refers to
Increased Platelet Destruction immune-mediated thrombocytopenias that are due to an
underlying disease or to drug exposure. (2)(3) The dis-
● Immune-mediated
–Immune thrombocytopenic purpura tinction between primary and secondary ITP is clinically
–Neonatal alloimmune thrombocytopenia relevant both in regard to prognosis and treatment.
–Neonatal autoimmune thrombocytopenia ITP is the most common immune-mediated throm-
–Autoimmune diseases bocytopenia in children, with an annual incidence of
–Drug-induced
symptomatic cases estimated to be between 3 and 8 cases
● Platelet activation/consumption
–Disseminated intravascular coagulation per 100,000 children. Pediatric patients who develop
–Hemolytic-uremic syndrome ITP usually present between the ages of 2 and 10 years,
–Thrombotic thrombocytopenic purpura with a peak incidence at 2 to 5 years. There does not
–Kasabach-Merritt syndrome appear to be a significant sex bias in childhood ITP.
–Necrotizing enterocolitis
(4)(5)
–Thrombosis
● Mechanical platelet destruction The typical case of symptomatic childhood ITP is
● Platelet sequestration characterized by the sudden appearance of bruising or
–Chronic liver disease mucocutaneous bleeding in an otherwise healthy child,
–Type 2B and platelet-type von Willebrand disease often after a preceding viral illness. An increased risk of
–Malaria
ITP is also associated with measles, mumps, rubella im-
Decreased Platelet Production munization, which accounts for perhaps 50% of all ITP
● Infection cases during the second year after birth. This form of ITP
● Cyanotic congenital heart disease tends to be transient and rarely is the bleeding severe.
● Bone marrow failure or infiltrate The history should reveal no systemic symptoms such
–Acute lymphoblastic leukemia and other as fever, weight loss, or bone pain. Other than muco-
malignancies
–Acquired aplastic anemia cutaneous bleeding, patients should appear well. No
–Fanconi pancytopenia lymphadenopathy or hepatosplenomegaly should be
● Nutritional deficiencies present. If one or more of these findings are present,
● Genetically impaired thrombopoiesis another diagnosis should be strongly considered. Other-
–Thrombocytopenia with absent radii syndrome wise, the diagnosis of ITP can be made based on two
–Congenital amegakaryocytic thrombocytopenia
–Wiskott-Aldrich syndrome criteria: 1) isolated thrombocytopenia with otherwise
–X-linked thrombocytopenia with thalassemia normal blood counts and PBS and 2) no clinically appar-
–Giant platelet disorders ent associated conditions that may cause thrombocyto-
–Bernard-Soulier syndrome penia.
–May-Hegglin/Fechtner/Epstein and Sebastian The severity of bleeding symptoms in childhood ITP
syndromes
is proportionate to the degree of thrombocytopenia.
Serious bleeding requiring transfusion is uncommon.
The presenting platelet count is usually less than
struction of platelets in infants and children is an 20!103/!L (20!109/L). This value probably is due to
immune-mediated process. Autoantibodies, drug- patients who have higher platelet counts, which are much
dependent antibodies, or alloantibodies may mediate less likely to lead to bleeding, never coming to medical
platelet destruction through interaction with platelet attention. Children who have ITP and platelet counts
membrane antigens, leading to increased platelet clear- greater than 30!103/!L (30!109/L) usually have few
ance from the circulation. or no symptoms and require no treatment other than
Primary ITP is an acquired immune-mediated disor- restriction of activity and avoidance of medications that
der characterized by isolated thrombocytopenia in the have antiplatelet or anticoagulant activity. For those
absence of any obvious initiating or underlying cause. whose platelet counts are below 30!103/!L (30!109/
(2)(3) Formerly, the abbreviation ITP stood for idio- L), treatment recommendations are based on the pres-
pathic thrombocytopenic purpura. The new terminology ence and severity of associated bleeding symptoms or the
reflects the current understanding of the immune- risk thereof. (4)(6)

ITP is now classified by duration into newly diag- nia. Mothers of infants who manifest unexplained neo-
nosed, persistent (3- to 12-month duration), and natal thrombocytopenia should be investigated for the
chronic (#12-month duration). (2)(3) Whereas ITP in presence of an autoimmune disorder because neonatal
adults typically has an insidious onset and follows a thrombocytopenia can sometimes be the presenting sign
chronic course, ITP in children is usually short-lived, of maternal disease. Clinical signs are consistent with
with about two thirds of patients making full and sus- isolated thrombocytopenia, as in NAIT.
tained recoveries within 6 months of presentation, with The risk of severe thrombocytopenia and ICH is
or without treatment. (2)(3) Children who have persis- greater in alloimmune than in autoimmune neonatal
tent or chronic ITP or who manifest any atypical features thrombocytopenia. Ninety percent of infants born to
should be referred to or discussed with a hematologist mothers who have ITP have safe (#50!103/!L
experienced in the assessment and treatment of children [50!109/L]) or normal platelet counts. (8) The risk for
who have ITP. severe thrombocytopenia in the infant generally corre-
Neonatal alloimmune thrombocytopenia (NAIT) is lates with the severity of ITP in the mother. Neonatal
an uncommon syndrome whose estimated incidence in thrombocytopenia may be predicted if the mother has
the general population is 1 in 1,000 to 5,000 births. The had a splenectomy for treatment of chronic refractory
condition is manifested by an isolated, transient, but ITP, the mother’s platelet count has been less that
potentially severe thrombocytopenia in the neonate due 50!103/!L (50!109/L) at some time during the preg-
to platelet destruction by maternal alloantibodies. NAIT nancy, or an older sibling has had neonatal thrombocy-
occurs when fetal platelets contain an antigen inherited topenia. (8) Platelet counts of infants born to mothers
from the father that the mother lacks. Fetal platelets that who have ITP often decrease sharply during the first
cross the placenta into the maternal circulation trigger several days after birth. The nadir typically occurs at 2 to
the production of maternal immunoglobulin (Ig) G 5 days of age, and infants should be monitored closely
antiplatelet antibodies against the foreign antigen. These during this time. (8)
antibodies recross the placenta into the fetal circulation Autoimmune diseases such as SLE can present in
and destroy the body’s platelets, resulting in fetal and childhood with isolated immune-mediated thrombocy-
neonatal thrombocytopenia (analogous to hemolytic dis- topenia, and the true diagnosis may not be apparent for a
ease of the newborn). In contrast to Rh sensitization, prolonged period of time. Autoimmune diseases occur
NAIT often develops in the first pregnancy of an at-risk more commonly in older children and have an insidious
couple. The most serious complication of NAIT is ICH, onset of symptoms and persistent thrombocytopenia
which occurs in approximately 10% to 20% of affected beyond 6 months from the time of presentation. In-
newborns, with up to 50% of these events occurring in frequently, other autoimmune-mediated cytopenias
utero. (7) The mother of a newborn who has NAIT is present coincidentally with thrombocytopenia. In partic-
asymptomatic, although she may have a history of previ- ular, Evans syndrome is characterized by a Coombs
ously affected pregnancies. Affected newborns typically (direct antiglobulin test)-positive hemolytic anemia in
present with signs consistent with severe thrombocyto- association with immune-mediated thrombocytopenia.
penia, including petechiae, bruising, and bleeding, but Antibody-mediated thrombocytopenia also occurs with
are otherwise healthy. Platelet counts are often less than antiphospholipid antibody syndrome and autoimmune
10!103/!L (10!109/L). The platelet count typically lymphoproliferative syndrome.
falls in the first few days after birth, but then rises over the Drug-induced thrombocytopenia is a rare cause of
next 1 to 4 weeks as the alloantibody concentration thrombocytopenia in children. Medications begun
declines. In families who have an affected infant, the rate within the past month are more likely to be the cause of
of recurrence is as high as 75% to 90%, and thrombocy- the thrombocytopenia than medications that have been
topenia in the second affected child is always as or more taken for longer periods of time. Drug-induced throm-
severe than in the first. (7) bocytopenia is typically caused by drug-dependent anti-
Neonatal autoimmune thrombocytopenia also can bodies formed against a new antigen on the platelet
occur. This disorder is mediated by maternal antibodies surface that is created by drug binding to a platelet
that react with both maternal and infant platelets. This surface protein. Heparin-induced thrombocytopenia,
pathologic mechanism occurs in maternal autoimmune which can be associated with severe thrombosis, is due to
disorders, including ITP and systemic lupus erythemato- the formation of antibodies against the heparin-platelet
sus (SLE). The diagnosis usually is apparent from the factor 4 complex. The platelet count in heparin-induced
mother’s medical history and maternal thrombocytope- thrombocytopenia is usually only moderately decreased.

Although this condition is more commonly seen in rhage requiring rapid and repeated red blood cell trans-
adults, heparin-induced thrombocytopenia has been fusions may lead to thrombocytopenia due to a “wash
described in children. Other drugs commonly used in out” phenomenon.
pediatrics that can cause thrombocytopenia include car-
bamazepine, phenytoin, valproic acid, trimethoprim/
PLATELET SEQUESTRATION AND TRAPPING. About
sulfamethoxazole, and vancomycin. Support for the di-
one third of the platelet mass is normally sequestered in
agnosis of drug-induced thrombocytopenia is provided
the spleen at any given time. A greater proportion of
by resolution of the thrombocytopenia within approxi-
platelets are sequestered in patients who experience hy-
mately 1 week of withdrawal of the offending drug.
persplenism, reducing the number of circulating platelets
and leading to thrombocytopenia. The survival of plate-
PLATELET ACTIVATION AND CONSUMPTION. In pa-
lets in persons who have hypersplenism is normal or near
tients who experience disseminated intravascular co-
normal. It is the pooling and unavailability of platelets
agulation (DIC) and the microangiopathic disorders
“trapped” in the spleen that is the problem. Leukopenia
hemolytic-uremic syndrome (HUS) and thrombotic
or anemia also may accompany a low platelet count
thrombocytopenic purpura (TTP), thrombocytopenia
caused by hypersplenism. Conditions in this category
occurs because of systemic platelet activation, aggrega-
include:
tion, and consumption (Table 2). More localized platelet
activationandconsumptioncontributestothethrombocy- ● Chronic liver disease with portal hypertension and
topenia seen in Kasabach-Merritt syndrome (KMS), ne-
congestive splenomegaly. Occasionally, isolated throm-
crotizing enterocolitis (NEC), and thrombosis in infants
bocytopenia may be the initial manifestation of this
and neonates. In infants who have KMS, thrombocyto-
type of chronic liver disease. The platelet count is
penia results from shortened platelet survival caused by
typically in the range of 50 to 100!103/!L (50 to
sequestration of platelets and coagulation activa-
100!103/L) and usually does not represent a clinically
tion in large vascular malformations of the trunk, extrem-
important problem.
ities, or abdominal viscera. Cutaneous vascular lesions ● Type 2B and platelet-type von Willebrand disease.
are noted at birth in approximately 50% of patients.
Thrombocytopenia in this disorder is caused by in-
Detection of visceral lesions requires imaging studies. All
creased removal of platelets from the circulation. In-
patients have severe thrombocytopenia, hypofibrinogen-
creased binding between larger von Willebrand factor
emia, elevated fibrin degradation products, and fragmen-
multimers and platelets leads to the formation of small
tation of red blood cells on PBS.
platelet aggregates that are cleared from the circula-
NEC is a syndrome of gastrointestinal necrosis that
tion, resulting in a lower platelet count.
occurs in 2% to 10% of infants whose birthweights are ● Malaria with hypersplenism. This diagnosis should be
less than 1,500 g. Thrombocytopenia is a frequent find-
considered in any child who has fever, splenomegaly,
ing and can result in significant bleeding. In the early
thrombocytopenia, and a history of recent travel to an
stages of NEC, declining platelet counts correlate with
endemic area.
the presence of necrotic bowel and worsening disease.
The primary mechanism of thrombocytopenia appears
to be platelet destruction, although the destruction is Decreased Production
not caused by laboratory-detectable DIC in most cases. Impaired platelet production may be due to loss of bone
Thrombosis in infants and neonates is often accompa- marrow space from infiltration, suppression or failure of
nied by thrombocytopenia. A thromboembolic disorder cellular elements, or a defect in megakaryocyte develop-
should be considered if the thrombocytopenia cannot be ment and differentiation. In this setting, examination of
explained by other conditions. the bone marrow generally shows decreases in the num-
ber of megakaryocytes. Causes of marrow dysfunction
MECHANICAL PLATELET DESTRUCTION. The use of ex- include:
tracorporeal therapies, such as extracorporeal membrane
oxygenation, cardiopulmonary bypass, hemodialysis, and ● Infection
apheresis, is associated with mechanical destruction of ● Cyanotic heart disease
platelets, which may result in thrombocytopenia. Ex- ● Bone marrow failure or infiltration
change transfusion also may reduce platelet number by ● Nutritional deficiencies
loss in the exchange effluent. Severe ongoing hemor- ● Genetic defects

hematology
Table 2. Disorders of Systemic Platelet Activation and Consumption
thrombocytopenia
Pathophysiology Clinical Features Diagnosis Treatment Prognosis
Disseminated intravascular Pathologic activation of coagulation Complication of underlying y Thrombocytopenia Only effective therapy is Varies, depending on the
coagulation (DIC) mechanisms, resulting in illnesses such as sepsis, y Fragmented RBCs reversal of underlying underlying disorder
extensive microvascular asphyxia, meconium y Prolonged PT, aPTT cause. and the extent of the
thrombosis leading aspiration, severe y Decreased plasma fibrinogen intravascular
to ischemia and end-organ respiratory distress y Increased FDPs Temporizing measures include: thrombosis, but
damage. syndrome, extensive • Platelet transfusions for regardless of cause is
trauma. bleeding, severe often grim, with 10%
Consumption of platelets and thrombocytopenia to 50% mortality.
coagulation factors and Symptoms include bleeding, • FFP to replenish
activation of fibrinolysis result in hypotension, increased coagulation and
hemorrhage. vascular permeability, and antithrombotic factors
shock.
Hemolytic-uremic syndrome Most cases preceded by episode of Seen predominantly in y Thrombocytopenia Supportive care. Mortality rate is 5% to
(HUS) bloody diarrhea due to verotoxin- children. Usually preceded y Fragmented RBCs 10%. Most survivors
producing Escherichia coli by episode of bloody y Increased BUN, creatinine Dialysis, as needed, until recover without major
O157H7. diarrhea. y Normal PT, aPTT evidence of recovering renal consequences. Small
y Normal plasma fibrinogen function. proportion of patients
Verotoxin enters bloodstream, Onset of illness characterized y Normal FDPs develops chronic renal
attaches to glomerular by pallor and oliguria with Antibiotic treatment not
recommended because it insufficiency.
endothelium, and inactivates the thrombocytopenia and
metalloprotease ADAMTS13, laboratory evidence of may stimulate further
responsible for cleaving very large microangiopathic verotoxin production.
multimers of vWF. Uncleaved hemolytic anemia and Platelet transfusions may
vWF initiates platelet aggregation ARF. worsen outcome.
and activation, resulting in
network of microthrombi in If diagnostic uncertainty
kidneys that lead to between HUS and TTP
fragmentation of RBCs, because of neurologic or
consumption of platelets, and other nonrenal involvement,
tissue ischemia. plasma exchange
recommended.
Less common form without diarrhea
possibly due to factor H
deficiency with uncontrolled
complement activation and
thrombosis after minor
endothelial injury.
Thrombotic thrombocytopenic Most commonly associated • Thrombocytopenia y Thrombocytopenia Daily plasma exchange using Mortality rate $95%
purpura (TTP) with inhibition of ADAMTS13 • Microangiopathic y Fragmented RBCs FFP reduces anti- for untreated cases
by autoantibodies. As in HUS, hemolytic anemia y Elevated LDH ADAMTS13 antibodies and but 10% to 20% for
without proper cleavage of vWF, • ARF y Increased BUN, creatinine replenishes concentrations patients treated early
spontaneous coagulation occurs. • Neurologic symptoms y Normal PT, aPTT of the enzyme. May be with plasma
In TTP, a network of • Fever y Normal plasma fibrinogen needed for 1 to 8 weeks exchange.
microthrombi in multiple organ y Normal FDPs before laboratory values
systems results in clinical and ARF and neurologic y Decreased (<5% of normal) normalize. Approximately 30% of
laboratory findings. Rarer form symptoms may not be ADAMTS13 activity patients experience a
called Upshaw-Schülman present initially. Fever y Detectable inhibitors of Upshaw-Schulman syndrome relapse within 10
syndrome is a genetically uncommon. Only ADAMTS13 patients receive FFP every years of the first
inherited dysfunction of thrombocytopenia and 2 to 3 weeks to maintain attack.
ADAMTS13. microangiopathic adequate concentrations of
hemolytic anemia without functioning enzyme.
other apparent cause
required to suspect
diagnosis.
aPTT%activated partial thromboplastin time, ARF%acute renal failure, BUN%blood urea nitrogen, FDP%fibrin degradation product, FFP%fresh frozen plasma, LDH%lactate dehydrogenase, PT%prothrombin time, RBC%red blood
cell, vWF%von Willebrand factor
INFECTION. Thrombocytopenia due to infections not immune-mediated destruction of hematopoietic stem

associated with evidence of DIC is usually caused by cells.
bone marrow suppression. In some cases, increased de- Fanconi pancytopenia syndrome is a rare autosomal
struction due to an infection-induced immune-mediated recessive disorder. The mean age at diagnosis of the
process or splenomegaly and reticuloendothelial hyper- pancytopenia is approximately 6 to 9 years, but the
activity may compound the problem of bone marrow condition may be recognized earlier by characteristic
suppression. The most common infectious agents asso- congenital malformations that are present in 60% to 70%
ciated with thrombocytopenia due to bone marrow sup- of affected patients. The most common malformations
pression are Epstein-Barr virus, cytomegalovirus, parvo- are hypopigmented macules, café-au-lait macules, abnor-
virus, varicella virus, and rickettsiae. In most cases, the malities of the thumbs, microcephaly, and urogenital
thrombocytopenia is transient, with recovery within a abnormalities. Short stature of prenatal onset may also be
period of weeks. Thrombocytopenia is a common find- seen.
ing in patients who are infected with the human immu-
nodeficiency virus (HIV), in whom both platelet destruc- NUTRITIONAL DEFICIENCIES. Folate, vitamin B12, and
tion and impaired production appear to play roles in iron deficiencies have been associated with thrombocy-
decreasing the platelet count. topenia. Folate and vitamin B12 deficiencies impair bone
marrow production, usually resulting in pancytopenia.
Iron deficiency, which can cause either thrombocytosis
CYANOTIC HEART DISEASE. Cyanotic congenital heart
or thrombocytopenia, appears to impair a late stage of
disease is associated with thrombocytopenia. The cause is
thrombopoiesis. Thrombocytosis and iron deficiency
unclear, but the mechanism appears to involve decreased
may be a response to gastrointestinal blood loss.
production of megakaryoctes.
GENETIC CAUSES OF IMPAIRED THROMBOPOIESIS. A
BONE MARROW FAILURE OR INFILTRATION. Throm- large number of rare inherited diseases present with
bocytopenia associated with anemia and leukopenia (ie, reduced platelet count, and many involve impaired plate-
pancytopenia) suggests general bone marrow dysfunc- let function as well. These conditions arise from genetic
tion or infiltration. Serious disorders such as leukemia or defects of the megakaryocyte lineage that result in im-
other malignancy, hemophagocytic lymphohistiocytosis, paired thrombopoiesis. The consideration of congenital
acquired aplastic anemia, myelodysplasia, and inherited thrombocytopenia should be greater in patients who
bone marrow failure syndromes such as Fanconi pancy- have a prolonged history of asymptomatic abnormal
topenia syndrome and dyskeratosis congenita can present platelet counts or a family history of thrombocytopenia.
with pancytopenia. General bone marrow dysfunction Some patients born with congenital thrombocytopenia
can also be caused by exposure to chemotherapeutic are followed for many years with the presumptive diag-
agents or radiation. nosis of ITP until another family member is discovered
Acute lymphoblastic leukemia is the most common to have a low platelet count. Table 3 outlines the genetic
childhood leukemia. Affected children usually have other causes of impaired thrombopoiesis.
clinical and laboratory findings besides thrombocytope-
nia. These manifestations include systemic symptoms Clinical Manifestations
such as fever, bone pain, and weight loss as well as Children who have thrombocytopenia may be asymp-
hepatosplenomegaly, lymphadenopathy, leukocytosis, tomatic or symptomatic. In asymptomatic patients,
and anemia. thrombocytopenia is often detected unexpectedly on a
Acquired aplastic anemia is a rare disorder caused by CBC obtained for another clinical issue. Symptomatic
profound, almost complete bone marrow failure. Specific patients generally present with mucosal or cutaneous
symptoms associated with acquired aplastic anemia vary bleeding.
but can include fever, fatigue, dizziness, weakness, head- Mucosal bleeding usually manifests as epistaxis, gin-
aches, and episodes of excessive bleeding. Pancytopenia gival bleeding or extensive oral mucous membrane
is often seen on presentation. Based on the response of bleeding (“wet purpura”), hematuria, or in postpubertal
approximately 50% of patients to immunosuppressive females, excessive menstrual bleeding. The presence of
medications, including antithymocyte globulin, cyclo- “wet purpura” is widely perceived as a risk factor for
sporine, high-dose corticosteroids, and cyclophosph- potentially life-threatening hemorrhage.
amide, most cases are now believed to be due to an Cutaneous bleeding usually appears as petechiae or

hematology
Table 3. Genetic Causes of Impaired Thrombopoiesis

thrombocytopenia
Diagnosis Inheritance Cause Clinical Features Laboratory Features Prognosis Treatment

Thrombocytopenia with Variable inheritance Unclear genetic cause. ● Severe thrombocytopenia ● Absent or markedly Mortality significant in ● Platelet transfusions
absent radii syndrome Possible defect of ● Bilateral absent radii decreased megakaryocytes infancy due to
megakaryocyte ● Normal thumbs ● Normal erythroid and intracranial hemorrhage.
maturation. Does not ● Other skeletal, genitourinary, myeloid maturation If patient survives,
involve either heart anomalies thrombocytopenia often
thrombopoietin or improves over next
thrombopoietin receptor. several years.
Congenital amegakaryocytic Autosomal recessive Mutations in ● Severe but isolated ● Absent or markedly Often progresses to ● Platelet transfusions
thrombocytopenia thrombopoietin receptor thrombocytopenia decreased megakaryocytes pancytopenia and ● Bone marrow
gene, leading to absent ● Normal erythroid and leukemic transformation transplantation
or dysfunctional myeloid maturation
thrombopoietin receptors.
Wiskott-Aldrich syndrome X-linked recessive Abnormal gene on proximal ● Atopic dermatitis ● Small (3 to 5 fL) defective Survival beyond teens rare. Splenectomy may improve
disorder arm of X chromosome ● Thrombocytopenic platelets Infections or bleeding are platelet count but often
encodes regulatory purpura ● Normal-appearing major causes of death. complicated by
protein of lymphocyte ● Increased susceptibility to megakaryocytes 12% incidence of fatal overwhelming sepsis/
and platelet function. infections malignancy. death
Giant platelet disorders Autosomal recessive Dysfunction/absence of ● Easy bruising and severe ● Macrothrombocytopenia, Bleeding tendency lifelong For both Bernard-Soulier,
● Bernard-Soulier platelet receptor for von hemorrhage with trauma/ severe platelet dysfunction MYH9RD: Desmopressin
syndrome Willebrand factor (GP Ib- surgery acetate may shorten
IX-V) bleeding time. Platelet
transfusions for
surgery/severe bleeding.
Bernard-Soulier patients
may develop
antiplatelet antibodies
because of GP Ib-IX-V
on transfused platelets.
● MYH9-related disease Autosomal dominant Nonmuscle myosin heavy ● Bleeding, nephritis, hearing ● Macrothrombocytopenia, Progressive high-frequency
(MYH9RD) chain gene (MYH9) loss, cataracts. Epstein, leukocyte inclusions, sensorineural hearing loss,
mutations Fechtner, Sebastian hematuria, proteinuria glomerulonephritis and
syndrome or May-Hegglin cataracts may develop
anomaly previously anytime between infancy
diagnosed based on specific and adulthood.
clinical findings at
presentation but now
regarded as one disorder.

superficial ecchymoses. Patients who have thrombocyto- performed at the site of indwelling catheters, drains, and
penia may also have persistent, profuse bleeding from incisions or areas of previous trauma. Table 4 lists the
superficial cuts. Petechiae, the pinhead-sized, red, flat, “red flags” in the history and physical examination of
discrete lesions caused by extravasation of red cells from children who have thrombocytopenia that should lead to
skin capillaries and often occurring in crops in dependent consideration of diagnoses other than ITP.
areas, are highly characteristic of decreased platelet num-
ber or function. Petechiae are nontender and do not Laboratory Evaluation
blanch under pressure. They are asymptomatic and not The laboratory evaluation of thrombocytopenia begins
palpable and should be distinguished from small telangi- with a CBC and evaluation of the PBS. Although a dying
ectasias and vasculitic (palpable) purpura. Purpura de- skill for most general practitioners, the ability to assess
scribes purplish discolorations of the skin due to the the PBS accurately is invaluable in the evaluation of
presence of confluent petechiae. Ecchymoses are non- children who have thrombocytopenia or other hemato-
tender areas of bleeding into the skin that are typically logic abnormalities. Consultation with a hematopatholo-
small, multiple, and superficial and can develop without gist or experienced laboratory technologist may be use-
noticeable trauma. Ecchymoses often have a variety of ful.
colors due to the presence of extravasated blood (red or The CBC should be examined closely for the platelet
purple) and the ongoing breakdown of heme pigment in count and mean platelet volume (MPV) as well as for
the extravasated blood by skin macrophages (green, yel- evidence of any other cytopenias (anemia or leukopenia).
low, or brown). A platelet count that does not make sense clinically
This pattern of bleeding differs from that of patients should be confirmed before undertaking extensive eval-
who have disorders of coagulation factors, such as hemo- uation to be sure that thrombocytopenia exists and the
philia. Patients who have thrombocytopenia tend to have finding is not due to artifact or laboratory error. Spurious
less deep bleeding into muscles or joints, more bleeding thrombocytopenia can be caused by improper collection
after minor cuts, less delayed bleeding, and less postsur- or inadequate anticoagulation of the blood sample, re-
gical bleeding. In addition, patients who have coagula- sulting in platelet clumps that are counted as leukocytes
tion factor disorders tend not to have petechiae. Al- by automated cell counters. Once thrombocytopenia
though rare, bleeding into the central nervous system is has been confirmed, an MPV that is significantly higher
the most common cause of death due to thrombocyto- than normal suggests one of the macrothrombocyto-
penia. When such bleeding occurs, it is often preceded by penia syndromes. A mildly elevated MPV is consistent
a history of head trauma. with a destructive cause. A low MPV is typically seen in
patients who have Wiscott-Aldrich syndrome (WAS)
Evaluation gene mutations.
A thorough history and physical examination and judi- The PBS should be examined to estimate the platelet
cious use of laboratory testing can lead to the appropriate number (1 platelet/high power field%platelet count of
diagnosis in most patients (Fig. 2). Patients should be $10!103/!L [10!109/L]), determine the platelet
questioned about past and current bleeding symptoms, morphology and the presence or absence of platelet
including bruising with little or no trauma, nosebleeds, clumping, and assess whether there are associated white
blood in the urine or stool, gum bleeding, bleeding with and red blood cell changes. Large platelets suggest either
surgical or dental procedures, or excessive menstrual an ongoing platelet destructive process leading to the
bleeding. Duration and onset of the bleeding symptoms production of younger and larger platelets or the pres-
may help determine whether the cause is acquired or ence of a congenital macrothrombocytopenia syndrome.
congenital. If thrombocytopenia is due to an acquired Small platelets in the appropriate clinical setting suggest
cause, the onset of symptoms may be linked to a specific WAS. The presence of schistocytes suggests a micro-
trigger (eg, infection). Congenital thrombocytopenia angiopathic process such as DIC, HUS, or TTP. Sphero-
should be considered in patients who have a prolonged cytes suggest autoimmune hemolytic anemia coupled
history of asymptomatic abnormal platelet counts or a with immune-mediated thrombocytopenia (Evans syn-
family history of thrombocytopenia. drome).
In children who have suspected or known thrombo- Other tests may be useful in determining the cause of
cytopenia, the skin, gingivae, and oral cavity should be the thrombocytopenia but are generally performed based
examined carefully for evidence of bleeding. In hospital- on suggestive findings from the initial history and phys-
ized patients, careful examination for bleeding should be ical examination and laboratory testing. A positive direct

Figure 2. Diagnostic algorithm for thrombocytopenia. CAMT!congenital amegakaryocytic thrombocytopenia, DIC!disseminated

intravascular coagulation, HUS!hemolytic-uremic syndrome, TAR!thrombocytopenia with absent radii syndrome, TTP!thrombotic
thrombocytopenic purpura, WAS!Wiscott-Aldrich syndrome.
Coombs test suggests an autoimmune process in a pa- Screening tests for inherited disorders associated with
tient who has evidence of hemolysis as well as spherocytes thrombocytopenia should be considered in patients who
on the PBS. For patients who have persistant or chronic experience chronic thrombocytopenia, especially in the
ITP, antinuclear antibody, serum immunoglobulins presence of short stature or other congenital anomalies.
(IgG, IgA, IgM), and antiphospholipid antibodies Platelet antibodies can be detected by a variety of
should be considered. Fibrin degradation products and assays. Although many of these assays have high sensitiv-
fibrinogen measurements are useful to diagnose intravas- ity, they lack specificity and are not indicated or per-
cular coagulation. formed routinely to confirm the diagnosis of acute ITP in
If the PBS results are consistent with a microangio- children.
pathic process, additional tests should be considered, A bone marrow examination is not necessary in most
including serum lactate dehydrogenase and creatinine to cases of isolated unexplained thrombocytopenia in chil-
assess for HUS or TTP. HIV testing should be consid- dren. In general, a bone marrow examination is indicated
ered because thrombocytopenia may be the initial disease when clinical signs or symptoms suggest either marrow
manifestation in as many as 10% of patients who have infiltration or failure. These findings include pancytope-
HIV infection. If clinical suspicion or local prevalence is nia; the presence of blasts on the PBS; and the presence
high, tests to identify hepatitis C viral infection or Heli- of systemic symptoms such as fever, fatigue, weight loss,
cobacter pylori infection should also be considered. or bone pain. A bone marrow examination also is indi-

cated for unexplained, chronic, stable thrombocytope-

nia, even when the presumed diagnosis is ITP, or if the Red Flags Suggesting a
Table 4.
subsequent clinical course is inconsistent with the natural
history of ITP because of the development of new clinical
Diagnosis Other Than Immune
signs or symptoms or laboratory abnormalities. Thrombocytopenic Purpura
Treatment History
Management of thrombocytopenia in an individual pa- ● Fever
tient should be guided by an understanding of its cause ● Bone pain
● Weight loss
and predicted clinical course. Correction of the cause ● Fatigue
may not be possible (eg, congenital thrombocytopenias) ● Recent history of infections or vaccinations
or may not be necessary (eg, mild-to-moderate ITP). ● Past medical history of diseases associated with
The principal management goal in all patients who have thrombocytopenia (eg, autoimmune disorders,
thrombocytopenia is to maintain a safe platelet count to cirrhosis)
● Dietary history suggestive of iron, vitamin B12, or
prevent significant bleeding, not to achieve a normal folate deficiency
platelet count. What constitutes a safe platelet count in a ● Exposure to medications known to be associated
particular patient varies, depending on the cause of the with thrombocytopenia
thrombocytopenia and consideration of all other aspects ● Travel history to an endemic area for malaria
of hemostasis. For patients who have significant bleeding Physical Examination
symptoms, treatment is essential. Asymptomatic or min- ● Lymphadenopathy
imally symptomatic thrombocytopenia may be treated if ● Splenomegaly
the thrombocytopenia is severe or the perceived risk of ● Joint swelling
bleeding is great. ● Short stature
● Limb defects, including radial agenesis and thumb
abnormalities
Activity Restrictions ● Cataracts
When moderate-to-severe thrombocytopenia is recog- ● Sensorineural hearing loss
nized, implementing reasonable precautions to minimize ● Oral leukoplakia
bleeding risk is recommended. These steps include ● Dystrophic nails
trauma precautions (eg, avoidance of contact sports and ● Eczema in male patient
● Frequent infections
use of a helmet while cycling) and avoidance of medica- ● Superficial hemangiomas
tions that have antiplatelet or anticoagulant activity (in-
cluding aspirin-containing preparations, ibuprofen, and
other nonsteroidal anti-inflammatory drugs).
patients who have destructive thrombocytopenias may
Invasive Procedures not be normal, platelet transfusion nearly always provides
A platelet count greater than 50!103/!L (50!109/L) prompt, satisfactory hemostasis, even if only for a short
provides safety for most invasive procedures. If the risks duration.
of potentially serious bleeding are believed to be severe,
a platelet count of greater than 100!103/!L (100! Emergency Management of Critical Bleeding
109/L) is often required by surgeons or anesthesiolo- Patients who have severe thrombocytopenia and critical
gists. For common minor procedures, such as tooth bleeding require immediate transfusion of platelets re-
extractions, a platelet count of 30 to 50!103/!L gardless of the cause of the thrombocytopenia. ICH is
(50!109/L) often is sufficient. (1) For patients who the most serious consequence of severe thrombocyto-
have lower platelet counts, some measure to increase the penia. Early diagnostic imaging should be considered
platelet count immediately before the procedure may be for patients who have severe thrombocytopenia and
required. A short course of corticosteroids (prednisone neurologic signs or symptoms to identify ICH. For
2 mg/kg per day for 1 week) or a single dose of immune patients who have unstable or progressive ICH, emer-
globulin intravenous (IGIV) (1 g/kg) is often sufficient gency craniotomy may be necessary. For patients who
to increase the platelet count acutely for procedural have ITP with life-threatening bleeding, in addition to
hemostasis. Platelet transfusions can be used in urgent platelets, adjunctive treatment with high doses of corti-
situations. Although platelet survival in the circulation of costeroid (intravenous methylprednisolone 30 mg/kg

hematology
Table 5.
Initial Treatment for Newly Diagnosed Immune Thrombocytopenic Purpura (ITP) With
Significant Bleeding or Risk of Bleeding
Treatment Mechanism of Action Response Rate Toxicities Comments
● ● ●
thrombocytopenia
Corticosteroids Reduces antibody production Up to 75% achieve platelet Behavioral changes No curative benefit known
Dosing varies from prednisone ● Reduces reticuloendothelial response, depending on ● Sleep disturbance ● Often, a drop in platelet
2 mg/kg per day orally for system phagocytosis of dose; response to therapy ● Increased appetite count after steroids

2 to 4 weeks to high-dose antibody-coated platelets usually within 2 to 7 days ● Weight gain discontinued
methylprednisolone 30 mg/kg ● Improves vascular integrity ● Gastritis/gastrointestinal ● Repeated courses may be
per day (maximum, 1 g) ● Improves platelet production hemorrhage necessary if significant
intravenously for 3 to 7 days ● Immunosuppression bleeding symptoms persist or
● Poor linear growth recur
Immune Globulin Intravenous Unknown and likely >80% achieve platelet ● Nausea/vomiting ● No curative benefit known
(IGIV) multifactorial. Theories response; response to ● Severe headache ● 30% have significant drop in
Single dose 1 g/kg include: therapy usually within ● Fever platelet count in 2 to
● Reticuloendothelial system 24 hours ● Chills 6 weeks
blockade/inhibition ● More pronounced in ● IGIV appears to improve
● Autoantibody older patients platelet counts more reliably
neutralization by anti- than corticosteroids or no
idiotype antibodies treatment. Some experts
● Increased autoantibody believe that in patients who
clearance due to fail to show any platelet rise
competitive inhibition of with IGIV, the diagnosis of
immunoglobulin Fc ITP should be reconsidered
receptor and bone marrow assessment
strongly considered
Anti-Rho(D) immune globulin Specific red blood cell 50% to 77% achieve platelet ● Hemolysis (can be ● With higher doses, is
Single dose 50 to 75 "g/kg antibodies coat red blood response, depending on severe) comparable to IGIV
cells, which are then taken up dose; up to 50% respond ● Disseminated ● Only effective in children who
by the reticuloendothelial within 24 hours intravascular are Rho(D)-positive. Should
system in place of antibody- coagulation only be given if hemoglobin
coated platelets ● Renal failure (rare) >10 g/dL (100 g/L) and
● Headache, fever, chills Coombs-negative. Treated
less common than with patients must be watched for
IGIV presence and sequelae of
significant hemolysis. IGIV is

generally preferred.
Table 6.
Treatment Options for Children Who Have Refractory Immune Thrombocytopenic
Purpura With Significant Bleeding Symptoms
Treatment Mechanism of Action Response Rate Toxicities Comments
Splenectomy Reduces destruction of both Usually raises the platelet ● Intraoperative bleeding Even those not demonstrating
autologous and transfused count within hours; ● Life-threatening infections rise in platelet count may
platelets 60% to 70% achieve a be more responsive to
permanent remission previously failed medical
therapies.
High-dose methylprednisolone ● Reduces antibody production >60% to 100% achieve ● Behavioral changes If repeated courses necessary,
30 mg/kg per day ● Reduces reticuloendothelial platelet response; ● Increased appetite alternative therapies should
(maximum, 1 g) for 3 days system phagocytosis of response to therapy ● Gastritis/gastrointestinal be considered.
followed by 20 mg/kg per antibody-coated platelets usually within 2 to hemorrhage
day for 4 days ● Improves vascular integrity 7 days ● Immunosuppression
● Improves platelet production ● Poor linear growth
● Decreased bone
mineralization
Single or combination Immunosuppression via $70% achieve platelet Usual adverse effects of Experience in children limited.
regimens: cyclosporin A, cytotoxic effects response; response to individual agents
azathioprine, vincristine, therapy varies but
cyclophosphamide, danazol generally days to
# prednisone, immune months
globulin intravenous (IGIV)
Rituximab 375 mg/m2 per Not completely defined. At least 30% complete Usually well tolerated with If thrombocytopenia recurs,
dose intravenously weekly Possibly, source of response rate lasting manageable infusion- second course appears to
for 4 weeks pathogenic antibodies (B an average of 13 related adverse effects. be safe and effective.
lymphocytes) removed by months; response is Hypogammaglobulinemia is
selective destruction of usually prompt (1 to infrequent. IGIV 400 mg/kg
CD20-positive cells, 2 weeks) but may take every 3 to 4 weeks may be
resulting in decreased up to 8 weeks. Delay administered to maintain
antibody production. may be result of time normal concentrations.
needed to clear Progressive multifocal
circulating pathogenic leukoencephalopathy has
antibodies. been reported, but causal
relationship not confirmed.
Thrombopoietin receptor Romiplostim, a subcutaneous As high as 80% in adult ● Thrombosis No effect on underlying
agonists thrombopoiesis-stimulating patients. Studies in ● Increased concentrations of pathologic mechanism, and
Romiplostim 1 to 10 "g/kg Fc peptide fusion protein, children extremely bone marrow reticulin rebound thrombocytopenia
hematology
subcutaneously weekly and eltrombopag, an orally limited. Use currently when drugs are stopped is
Eltrombopag 25 to 75 mg active, nonpeptide restricted to refractory common. Used to keep

orally daily thrombopoietin receptor patients who have platelets in safe range
agonist, act by stimulating significant bleeding (50 to 200$103/"L [50 to
platelet production. symptoms. 200$109/L]). Very
expensive, and long-term
experience limited.
thrombocytopenia

up to 1 g/day for 3 days) and a single dose of IGIV roids, IGIV, and anti-Rho(D) immune globulin (Table
(1 g/kg) is also appropriate. Emergency splenectomy 5). Several studies have shown that the duration of
may be considered in cases of refractory ITP accompa- symptomatic thrombocytopenia is shortened by any of
nied by life-threatening hemorrhage. these three interventions compared with no treatment.
All ITP therapies are temporizing interventions intended
Thrombocytopenia Associated With Other for rapid reversal of a real or perceived risk for significant
Cytopenias hemorrhage. They do not need to be continued until
Patients who have pancytopenia with systemic symptoms normal platelet counts are reached. Therapy is targeted
or significant findings on examination should be evalu- to increase the platelet count above a threshold (usually
ated carefully in a timely manner because they are at #20!103/!L [20!109/L]) that stops bleeding or
increased risk for a serious disorder that may require eliminates the risk of serious bleeding. (6) Platelet trans-
urgent intervention. Consultation with a pediatric hema- fusions are indicated in patients who have ITP only in
tologist should be strongly considered. Treatment of the the setting of life-threatening bleeding, such as ICH.
identified underlying primary disorder guides subse- Because of accelerated platelet destruction in ITP, plate-
quent management. For such patients, maintenance of a let transfusions result in a relatively limited rise in the
safe platelet count may be only a small part of the overall platelet count of very short duration (measured in hours
treatment plan. or even minutes) that may be adequate for the immediate
hemostasis required in the setting of ICH but otherwise
Isolated Thrombocytopenia is of no benefit.
The most likely diagnosis in an otherwise healthy child Almost all children who develop ITP are treated in the
who has isolated thrombocytopenia is ITP. Most patients ambulatory setting. Patients who require pharmacologic
do not have serious bleeding (including those whose intervention with IGIV or high-dose intravenous corti-
platelet counts are &10!103/!L [10!109/L]). ICH is costeroids are usually hospitalized for an average of 1 to
extremely rare, with an incidence of 0.1% to 0.5%. Al- 3 days. Platelet counts are monitored once or twice
though treatments for childhood ITP may reduce the weekly, depending on the clinical situation and severity
severity and duration of the initial thrombocytopenic of the thrombocytopenia. When recovery of platelet
episode and presumably the risk of bleeding, they do not counts is detected, the interval between platelet count
appear to affect the eventual recovery rate. Up to two assessment may be lengthened. Monitoring should con-
thirds of children who have ITP recover within 6 months tinue until the platelet count has returned to normal and
of presentation with or without treatment. (3)(5) is stable.
Most experts agree that pharmacologic intervention Approximately 20% to 30% of children who present
is not generally needed for children who have mild-to- with ITP eventually develop chronic ITP, defined as
moderate thrombocytopenia (platelet counts #30! persistent thrombocytopenia beyond 12 months from
103/!L] 30!109/L]) because they are unlikely to have the time of presentation. Patients who have chronic ITP
serious bleeding. Exceptions to this policy include chil- are usually clinically indistinguishable from those who
dren who have concomitant or preexisting conditions have acute ITP at presentation. Children younger than
that increase their risk for severe bleeding and children 10 years of age are more likely to have remissions than
undergoing procedures likely to include blood loss. (6) older patients. Children whose bleeding manifestations
For patients whose platelet counts are less than last more than 14 days are substantially more likely to
30!103/!L (30!109/L), treatment recommendations develop chronic ITP.
are based on the presence and severity of associated All children who have persistent (3 to 12 months) or
bleeding or the risk thereof. Although there is no defined chronic (#12 months) ITP should have their cases re-
means to predict which children who have ITP will suffer viewed and managed by a pediatric hematologist. Indi-
from an ICH, retinal hemorrhages and extensive muco- viduals who have chronic ITP should undergo evaluation
sal bleeding or “wet purpura” have been reported to that includes bone marrow examination to exclude other
precede and possibly predict spontaneous ICH. (4) causes of thrombocytopenia. In chronic ITP, platelet
Thus, any individual who has ITP and actual or obvious counts tend to range between 20 and 75!103/!L
potential for significant bleeding requires immediate (20 and 75!109/L); consequently, many patients re-
treatment, regardless of the platelet count. quire no or only intermittent treatment for episodes of
When therapy is indicated, the primary treatment significant bleeding or increased risk of bleeding.
options for the newly diagnosed patient are corticoste- A small percentage of pediatric patients who have ITP

Pulse intermittent high-dose corticosteroids and sple-

Summary nectomy have been the mainstays of treatment in these
situations, although not without significant risks. Newer
• Thrombocytopenia should be suspected in any child treatment modalities that may be useful include ritux-
presenting with a history of easy bruising or
imab, a chimeric anti-CD20 monoclonal antibody, and
bleeding or petechiae, but it also may present as an
incidental finding in an asymptomatic individual. the thrombopoietin receptor agonists romiplostim and
• Thrombocytopenia may be caused by either increased eltrombopag, although studies of these agents in chil-
destruction or removal of platelets from the dren are limited (9)(10)(11) and not approved by the
circulation or decreased production of platelets. United States Food and Drug Administration for chil-
• Destructive mechanisms resulting in
thrombocytopenia include immune-mediated dren younger than 18 years. The recent use of thrombo-
destruction, platelet activation and consumption, poietin receptor agonists reflects a new paradigm in the
mechanical platelet destruction, and platelet treatment of ITP, with the focus not on reducing platelet
sequestration or trapping. consumption through immune modulation or suppres-
• Impaired platelet production may be due to bone
marrow infiltration, suppression, or failure or defects
sion but on increasing platelet production.
in megakaryocyte development and differentiation.
• A thorough history and physical examination and
judicious use of laboratory testing can lead to the
appropriate diagnosis in most patients who have References
thrombocytopenia. 1. Slichter SJ. Relationship between platelet count and bleeding
• Childhood ITP generally presents with the sudden risk in thrombocytopenic patients. Transfus Med Rev. 2004;18:
appearance of bruising, bleeding, or petechiae in an 153–167
otherwise healthy child. 2. Rodeghiero F, Stasi R, Gemsheimer T, et al. Standardization of
• The diagnosis of ITP can be made using two criteria: terminology, definitions and outcome criteria in immune thrombo-
1) isolated thrombocytopenia with otherwise normal cytopenic purpura of adults and children: report from an interna-
blood counts and peripheral blood smear and 2) no tional working group. Blood. 2009;113:2386 –2393
clinically apparent associated conditions that may 3. Provan D, Stasi R, Newland A, et al. International consensus
cause thrombocytopenia. report on the investigation and management of primary immune
• Further evaluation, including bone marrow thrombocytopenia. Blood. 2010;115:168 –186
assessment, should be considered in patients who 4. Medeiros D, Buchanan GR. Current controversies in the man-
have atypical clinical or laboratory features at agement of idiopathic thrombocytopenic purpura during child-
presentation; thrombocytopenia lasting more than 6 hood. Pediatr Clin North Am. 1996;43:757–772
months; or a subsequent clinical course that is 5. Kuhne T, Buchanan GR, Zimmerman S, et al. A prospective
inconsistent with the natural history of ITP, comparative study of 2540 infants and children with newly diag-
including failure to respond to usually effective
nosed idiopathic thrombocytopenic purpura (ITP) from the In-
therapies.
tercontinental Childhood ITP Study Group. J Pediatr. 2003;143:
• Management of thrombocytopenia should be guided
605– 608
by an understanding of its cause and clinical course,
6. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombo-
with the principal goal in all patients being to
cytopenic purpura: a practice guideline developed by explicit
maintain a safe platelet count to prevent significant
methods for the American Society of Hematology. Blood. 1996;
bleeding.
• For childhood ITP, pharmacologic intervention, 88:3– 40
including corticosteroids, IGIV, and anti-Rho(D) 7. Bussel JB, Zabusky MR, Berkowitz RL, et al. Fetal alloimmune
immune globulin, has been shown to raise the thrombocytopenia. N Engl J Med. 1997;337:22–26
platelet count more quickly than no therapy and is 8. Payne SD, Resnik R, Moore TR, et al. Maternal characteristics
recommended for children who have or at risk for and risk of severe neonatal thrombocytopenia and intracranial hem-
severe or life-threatening bleeding, based on strong orrhage in pregnancies complicated by autoimmune thrombocyto-
evidence. penia. Am J Obstet Gynecol. 1997;177:149 –155
• ITP in children usually is short-lived, with at least 9. Wang J, Wiley JM, Luddy R, et al. Chronic immune thrombo-
two thirds of patients making a full and sustained cytopenic purpura in children: assessment of rituximab treatment.
recovery within 6 months of presentation, with or J Pediatr. 2005;146:217–221
without treatment. 10. Bennett CM, Rogers ZR, Kinnamon DD, et al. Prospective
phase I/II study of rituximab in childhood and adolescent
chronic immune thrombocytopenic purpura. Blood. 2006;107:
2639 –2642
and significant hemorrhagic symptoms demonstrate re- 11. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of
sistance to both corticosteroids and IGIV. Management long-term treatment with romiplostim in thrombocytopenic pa-
of such so-called refractory ITP is difficult (Table 6). tients with chronic ITP. Blood. 2009;113:2161–2171

PIR Quiz
Quiz 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 other
complaints. He has mild bruising but no petechiae and no mucosal bleeding. His physical examination
findings 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 most
appropriate 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). The
most 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 her
physical 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), and
absolute 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 vehicle
accident and arrives in the emergency department unresponsive. Emergency computed tomography scan of
the head reveals a large subdural hematoma. The child’s blood type is A-negative. The platelet count is
1$103/"L (1$109/L). You administer a platelet transfusion and high doses of intravenous
methylprednisolone and begin intravenous gamma globulin. During the emergency craniotomy, it is difficult
to 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).

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 as
well as mucosal petechiae. Laboratory results include a platelet count of 3$103/"L (3$109/L), hemoglobin
of 7.8 g/dL (78 g/L), white blood cell count of 12.9$103/"L (12.9$109/L), absolute neutrophil count of
8.8$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.
Corrections
The caption for Figure 2 in the article entitled “Focus on Diagnosis: Urine Electrolytes” in
the February issue of the journal (Pediatr Rev. 2011;32:65– 68) is incorrect. The correct
caption should read, “A graphic illustration of a positive urine anion gap, with the number
of unmeasured anions exceeding the number of unmeasured cations. When this situation
occurs 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 the
error.
The caption for Figure 1 in the article entitled “Sacral Dimples” in the March issue of
the 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 need
for further evaluation. . . .” We regret the error.

Deborah M. Consolini
Pediatrics in Review 2011;32;135
DOI: 10.1542/pir.32-4-135
Updated Information & including high resolution figures, can be found at:
Services http://pedsinreview.aappublications.org/content/32/4/135
References This article cites 11 articles, 5 of which you can access for free at:
http://pedsinreview.aappublications.org/content/32/4/135#BIBL
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Hematology/Oncology
http://pedsinreview.aappublications.org/cgi/collection/hematology:on
cology_sub
Blood Disorders
http://pedsinreview.aappublications.org/cgi/collection/blood_disorder
s_sub
Rheumatology/Musculoskeletal Disorders
http://pedsinreview.aappublications.org/cgi/collection/rheumatology:
musculoskeletal_disorders_sub
Collagen Vascular & Other Multisystem Disorders
http://pedsinreview.aappublications.org/cgi/collection/collagen_vasc
ular_-_other_multisystem_disorders_sub
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://pedsinreview.aappublications.org/site/misc/Permissions.xhtml
Reprints Information about ordering reprints can be found online:
http://pedsinreview.aappublications.org/site/misc/reprints.xhtml

care unit (NICU). Because of the nature of illnesses requiring When one or more infants are lost in a multiple-gestation
a stay in the NICU, the opportunity for the parents and pregnancy, an added layer of emotional and logistical diffi-
newborn to have physical contact and begin the attachment culty is added. Parents have reported having difficulties
process may be limited. Studies examining attachment in the attaching to the surviving children and noted feelings of
NICU have found that mothers and fathers may perceive ambivalence, shock, and disassociation. On the other hand,
their attachment differently and that simple changes can be some parents have responded by overly attaching to their
made to promote attachment. Although the mother’s sense of surviving infant(s). After a neonatal loss, some mothers have
attachment may be focused on the physical contact between a hard time developing an attachment during a future preg-
her and her infant, fathers are more likely to feel attachment nancy for fear of losing this infant as well and being heart-
through looking at the infant, taking pictures, and observing broken once again. Often families do not feel safe to begin the
the bond between mother and infant. To promote attachment, attachment process until the infant is actually born.
caring attitudes by nurses and physicians, open and regular Measures taken to help parents bond with infants from
communication, and allowing for rooming-in so that parents birth throughout childhood are important for healthy devel-
can provide care for the infant with some supervision from opment and growth. Children who have secure attachment
staff before discharge are all positive interventions. to a consistent and sensitive caregiver have a stronger
Another situation that may make attachment more of foundation for developing other healthy and strong relation-
a challenge for parents is when twins, triplets, or higher-order ships in the future. Parents who are emotionally available to
multiples are born. All parents have some anxiety and fear their children promote lifelong well-being and health.
about their newborn, but these feelings can be intensified COMMENT: Given long-standing cultural prejudices, it is
with multiple births and can interfere with the caregivers’ not surprising that attachment theory initially focused
ability to bond with their infants. In addition, it is not un- exclusively on mothers. After all, mothers were responsible
common for one or more of multiple newborns to be ill, for autism, weren’t they? Fortunately, we can learn, through
leading to some of the issues mentioned above surrounding evidence, to identify and then correct our prejudices. We
NICU care. Bonding and attachment may vary between the have long recognized that maternal depression and other
caregivers and the infants, with each parent feeling attached to mental health problems can significantly affect a child’s
one infant more than another. This is even more common if well-being and development, but only recently have studies
one infant remains hospitalized while the other(s) are at home. examined the possible effect of a father’s mental health on
If an infant dies, either through stillbirth or neonatal his child’s emotional growth and behavior. As with attach-
death, the response to the grieving family by the medical ment, it turns out that fathers count. A father’s mental health
care team is very important in the healing process. In surveys can indeed influence a child’s emotional and behavioral
of families who have lost a child, emotional support, open development: children living with a father who is depressed
communication, and the opportunity to hold their infant have or has other mental health problems are at increased risk for
all been reported as beneficial in the grieving process. Fur- emotional and behavioral problems of their own.
thermore, services such as photography, creation of hand and
foot molds, and help with final arrangements are often – Henry M. Adam, MD
provided to help the family remember and honor their loss. Editor, In Brief
NOTICE OF RETRACTION
Deborah M. Consolini, Thrombocytopenia in Infants and Children, Pediatrics in Review. 2011;32;135 (American Academy of
Pediatrics). The American Academy of Pediatrics has removed this article from circulation because it contained citation
and attribution errors. The journal apologizes to our readers and the authors of any sources that were not correctly cited.
ANSWER KEY FOR JANUARY 2015 PEDIATRICS IN REVIEW:

Acute Poststreptococcal Glomerulonephritis: 1. A; 2. B; 3. A; 4. E; 5. A.
Epigenetics in Pediatrics: 1. C; 2. A; 3. A; 4. A; 5. B.
The Patient-Parent-Pediatrician Relationship: 1. C; 2. D; 3. D; 4. B; 5. A.
42 Pediatrics in Review
Deborah M. Consolini
Pediatrics in Review 2011;32;135
DOI: 10.1542/pir.32-4-135
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/32/4/135
An erratum has been published regarding this article. Please see the attached page for:
http://pedsinreview.aappublications.org/http://pedsinreview.aappublications.org/content/36/1/42.full.pd
f
Data Supplement at:

http://pedsinreview.aappublications.org/content/suppl/2014/10/20/32.4.135.DC1.html
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601.

Thrombocytopenia: in Infants and Children

Uploaded by

Copyright:

Available Formats

Thrombocytopenia: in Infants and Children

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Thrombocytopenia: in Infants and Children

Uploaded by

Copyright:

Available Formats

Article hematology

Thrombocytopenia in Infants and Children

Pediatrics in Review Vol.32 No.4 April 2011 135

often asymptomatic with normal

bocytopenia, with platelet counts between 30 and ● Mechanical platelet destruction

atic (ie, easy bruising or bleeding), even with significant

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

mediated nature of the disease and the absence or mini-

Pediatrics in Review Vol.32 No.4 April 2011 137

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

Pediatrics in Review Vol.32 No.4 April 2011 139

Pathophysiology Clinical Features Diagnosis Treatment Prognosis

INFECTION. Thrombocytopenia due to infections not immune-mediated destruction of hematopoietic stem

Pediatrics in Review Vol.32 No.4 April 2011 141

Table 3. Genetic Causes of Impaired Thrombopoiesis

Diagnosis Inheritance Cause Clinical Features Laboratory Features Prognosis Treatment

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

Downloaded from http://pedsinreview.aappublications.org/ at Instituto Nacional de Pediatria on January 22, 2015

Pediatrics in Review Vol.32 No.4 April 2011 143

Figure 2. Diagnostic algorithm for thrombocytopenia. CAMT!congenital amegakaryocytic thrombocytopenia, DIC!disseminated

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

cated for unexplained, chronic, stable thrombocytope-

Pediatrics in Review Vol.32 No.4 April 2011 145

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

Downloaded from http://pedsinreview.aappublications.org/ at Instituto Nacional de Pediatria on January 22, 2015

Downloaded from http://pedsinreview.aappublications.org/ at Instituto Nacional de Pediatria on January 22, 2015

Pediatrics in Review Vol.32 No.4 April 2011 147

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

Pulse intermittent high-dose corticosteroids and sple-

Pediatrics in Review Vol.32 No.4 April 2011 149

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

Pediatrics in Review Vol.32 No.4 April 2011 151

Downloaded from http://pedsinreview.aappublications.org/ at Instituto Nacional de Pediatria on January 22, 2015

ANSWER KEY FOR JANUARY 2015 PEDIATRICS IN REVIEW:

Data Supplement at:

Downloaded from http://pedsinreview.aappublications.org/ at Instituto Nacional de Pediatria on January 22, 2015

You might also like