Immune thrombocytopenia (ITP) in children:

Clinical features and diagnosis

Author: James B Bussel, MD
Section Editor: Sarah O'Brien, MD, MSc
Deputy Editor: Carrie Armsby, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2024. | This topic last updated: May 30, 2024.

INTRODUCTION

Immune thrombocytopenia (ITP) of childhood is characterized by isolated

thrombocytopenia (platelet count <100,000/microL with normal white blood cell
count, hemoglobin, and blood smear) ( table 1). The cause of ITP remains
unknown in most cases, but it can be triggered by a viral or environmental trigger
or it may be secondary to an underlying immunologic defect [1-3]. ITP was
previously known as idiopathic thrombocytopenic purpura or immune
thrombocytopenic purpura. The current term Immune ThrombocytoPenia
preserves the widely-recognized acronym "ITP," while acknowledging the immune-
mediated mechanism of the disorder and that patients may have little or no signs
of purpura or bleeding [1].

The clinical features and diagnosis of ITP in children will be reviewed here. The
initial treatment of newly diagnosed ITP and management of chronic ITP in children
are discussed separately. (See "Immune thrombocytopenia (ITP) in children:
Management of newly diagnosed patients" and "Immune thrombocytopenia (ITP)
in children: Management of patients with persistent, chronic, or refractory
disease".)

TERMINOLOGY

The following terms are used throughout this topic:

 ● Primary ITP – ITP in the absence of other causes or disorders that are
associated with the immune-mediated thrombocytopenia is known as primary
ITP and is the main focus of this topic review.
● Secondary ITP – Secondary ITP refers to immune-mediated thrombocytopenia
with an underlying cause, including drug-induced or associated with systemic
illness, such as systemic lupus erythematosus (SLE), infection (eg, HIV), immune
deficiency (eg, common variable immunodeficiency [CVID] or autoimmune
lymphoproliferative syndrome [ALPS]), and other causes. Secondary causes of
immune-mediated thrombocytopenia are outlined briefly below. (See
'Differential diagnosis' below.)

Primary ITP is categorized into three phases, depending on duration [1]:

● Newly diagnosed ITP – ITP within three months from diagnosis (ie, from the
first low platelet count)
● Persistent ITP – ITP between 3 and 12 months after diagnosis
● Chronic ITP – ITP lasting for more than 12 months

PATHOGENESIS

In ITP, autoantibodies (usually immunoglobulin G) are directed against platelet

membrane antigens, such as the glycoprotein (GP) IIb/IIIa complex [4,5]. Antibodies
may be directed against other targets such as GP Ib/IX, GP Ia/IIa, GP V, and GP VI.
The antibody-coated platelets have a shortened half-life because of accelerated
clearance by tissue macrophages, predominantly those in the spleen. In addition,
the same antibodies may inhibit platelet production. The net effect is a decrease,
often substantial, in the platelet count.

Approximately 60 percent of children with ITP have detectable antiplatelet

antibodies. In patients without detectable antibodies, the mechanism is still
presumed to be immune-mediated. Thus, measurement of antiplatelet antibodies
is generally not helpful in diagnosing ITP, because the test is neither sensitive nor
specific. (See 'No role for antiplatelet antibody testing' below.)

In a subset of patients with ITP, whether or not antibodies are demonstrable, an

alternative immunologic mechanism of T cell-mediated cytotoxicity may cause
thrombocytopenia. These cytotoxic T cells may act upon megakaryocytes in the
bone marrow rather than circulating platelets. It is not known how often this
occurs, nor whether cytotoxic T cells play a role in the typical patient with ITP, nor
whether their primary role involves platelet destruction during passage through
the spleen or in the marrow.

Mechanisms rupturing self-tolerance play a role as well. These mechanisms involve

regulatory T cells (Tregs) and B cells (eg, checkpoint disruptions).

Our understanding of the pathogenesis of ITP is based largely on studies in adult

patients; there is less information available specifically on the pathogenesis of ITP
in children. The pathogenesis of ITP is discussed in greater detail separately. (See
"Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis",
section on 'Pathogenesis'.)

EPIDEMIOLOGY

ITP is one of the most common causes of symptomatic thrombocytopenia in

children. The annual incidence of ITP is estimated to be between 1 and 6.4 cases
per 100,000 children [3,6]. This figure is probably an underestimate because it is
based primarily upon patients that develop symptomatic thrombocytopenia,
particularly those who require hospitalization.

Children with ITP can present at any age, but there is a peak in incidence between
two and five years and a second smaller peak in adolescence. In a prospective
population-based study from the five Nordic countries (Sweden, Finland, Norway,
Denmark, and Iceland) between 1998 and 2000, the annual incidence of ITP was 4.8
per 100,000 children younger than 15 years of age [7]. One-half of the patients
were between one and four years of age, and approximately 80 percent were
younger than eight years of age.

In childhood ITP, there is a slight predominance of boys to girls, especially in

infants. In the largest case series of children with ITP from the registry of the
Intercontinental Childhood ITP Study Group that included >2000 infants and
children from 3 months to 16 years old. In infants between 3 and 12 months of age,
the male-to-female ratio was 1.7:1 [8]. The male predominance was minimal in
older children, such that the overall male-to-female ratio in this pediatric cohort
was 1.2:1 [9]. By contrast, there is a female predominance of ITP in adolescents and
younger adults ages 12 to 45 years. One hypothesis to explain the female
predominance in adolescents is the theory that higher levels of estrogen promote
autoimmunity. (See "Immune thrombocytopenia (ITP) in adults: Clinical
manifestations and diagnosis", section on 'Epidemiology'.)

Seasonal fluctuations have been reported, with a peak incidence of ITP occurring in
the spring and early summer in temperate climates [7,9]. This observation supports
the notion that viral triggers are an important cause of ITP; however, the finding
has not always been consistent. An association with allergic diseases (eg, allergic
rhinitis and atopic dermatitis) has also been reported [10].

CLINICAL FEATURES

ITP typically presents with the sudden appearance of a petechial rash ( picture 1),
bruising, and/or bleeding in an otherwise healthy child ( table 1).
Thrombocytopenia is occasionally detected incidentally if a complete blood count
(CBC) with platelets is performed for another reason (eg, preoperatively or on a
routine check-up).

Preceding illness or vaccination — Approximately 60 percent of children with

newly diagnosed ITP have a history of a preceding viral illness within the past
month [7,8]. Numerous viruses have been identified as triggers of ITP, including
Epstein-Barr virus, influenza, varicella zoster virus, cytomegalovirus, and HIV [11].
ITP occurring in association with coronavirus disease 2019 (COVID-19) has been
described [12]. In addition, for children with an established diagnosis of ITP,
infections can precipitate a relapse or drop in platelet count.

There is a very small increased risk of developing ITP in the six weeks following a
measles, mumps, and rubella (MMR) vaccination. MMR-associated ITP is rare,
occurring in approximately 2.6 cases per 100,000 doses of vaccine. (See "Measles,
mumps, and rubella immunization in infants, children, and adolescents", section on
'Adverse effects'.)

Early childhood vaccines other than MMR do not appear to be associated with
increased risk of ITP [13]. There have been case reports of ITP following
administration of varicella, hepatitis A, pneumococcus, and tetanus-diphtheria-
acellular pertussis vaccines in older children [13]. However, because of the small
number of exposed cases and potential confounding, the association of ITP with
these vaccines has not been confirmed.

Vaccine-associated thrombocytopenia secondary to COVID-19 vaccination is very

rare, as discussed separately. (See "COVID-19: Vaccine-induced immune thrombotic
thrombocytopenia (VITT)".)

Lack of systemic signs and symptoms — Other than mucocutaneous bleeding,

patients usually appear well and systemic symptoms are generally absent.

The history should explore the following, which are generally absent in children
with ITP at onset of their disease:
● Systemic symptoms (eg, fever, anorexia, bone or joint pain, weight loss,
gastrointestinal [GI] symptoms, headaches).
● Exposure to thrombocytopenia-inducing drugs ( table 2).
● Prior history of bleeding – Occasionally, a child with ITP will have a history of
bruising or bleeding stretching back one to six months, during which it
appears that the ITP was already active.
● Family history of bleeding or autoimmune disease.

On physical examination, there is no significant enlargement of lymph nodes, liver,

or spleen, although the spleen may be mildly enlarged in as many as 10 percent of
cases. Syndromic findings on examination should prompt consideration of an
inherited thrombocytopenia syndrome rather than ITP. (See "Causes of
thrombocytopenia in children", section on 'Inherited platelet disorders'.)

If any of these features are present, including mild splenomegaly, other causes of
thrombocytopenia should be carefully considered and appropriate testing pursued.
(See 'Differential diagnosis' below and 'Further evaluation' below.)

Bleeding symptoms — Most patients who present for medical attention have signs
of cutaneous bleeding (eg, petechiae ( picture 1), purpura, ecchymoses, and oral
mucosal bleeding); serious hemorrhage is fortunately very infrequent.

Grading of severity — Bleeding signs and symptoms in children with ITP can
range from none or minimal (eg, several small groups of petechiae or small
bruises) to severe and life-threatening (eg, intracranial hemorrhage or severe GI or
genitourinary bleeding) [14]. The Buchanan and Adix bleeding score is commonly
used to objectively characterize bleeding symptoms in patients with ITP ( table 3).
Other scales include the ITP bleeding scale and the Bleeding Assessment Tool.

More severe bleeding symptoms at the time of presentation (eg, Grade 3b or

higher on the modified Buchanan and Adix bleeding score ( table 3)) is associated
with increased risk of subsequent severe bleeding complications. This is discussed
separately. (See "Immune thrombocytopenia (ITP) in children: Management of
newly diagnosed patients", section on 'Disease course'.)

Mucocutaneous bleeding — At presentation, more than one-half of affected

children have only cutaneous bleeding (also referred to as "dry" purpura), including
petechiae ( picture 1), purpura, and ecchymoses [7].

Mucosal bleeding (also referred to as "wet" bleeding) may be present in as many as

40 percent of children with newly diagnosed ITP and typically involves the nasal
passages as well as buccal and gingival surfaces (as shown in panel B ( picture 2)).

Less often, mucosal bleeding may arise from the GI, genitourinary, or vaginal
tracts; this type of bleeding is more serious. Conjunctival or retinal hemorrhages
are infrequently seen [15].

The severity of presenting symptoms is generally commensurate with the degree of

thrombocytopenia, but many children have minimal bleeding even when platelet
counts are very low. In one large cohort study, mucosal bleeding was more
common with platelet counts <10,000/microL compared with ≥15,000/microL (51
versus 19 percent) [7].

In a large registry study of children with newly diagnosed ITP, the following
bleeding manifestations were reported [15]:
● Cutaneous (petechiae, purpura, or bruising) – 86 percent
● Oral – 19 percent
● Nasal – 20 percent
● No bleeding – 9 percent
● Menstrual, GI, or urinary bleeding – <3 percent

Serious hemorrhage — Serious bleeding (defined as epistaxis >5 to 15 minutes

duration, GI bleeding, other severe mucosal bleeding requiring hospital admission,
and/or blood transfusions) develops in approximately 3 percent of children with
newly diagnosed ITP [7,16-18]. Intracranial hemorrhage (ICH) occurs in
approximately 0.5 percent.

Factors associated with increased risk of serious bleeding include [16]:

● Severe thrombocytopenia (variably defined as platelet count <10,000/microL or
<20,000/microL, depending on the study). In most studies, nearly all severe
bleeding events occurred in children with very low platelet counts; however,
most patients with platelet counts in this range do not experience severe
bleeding events. (See "Immune thrombocytopenia (ITP) in children:
Management of newly diagnosed patients", section on 'Bleeding
complications'.)
● Previous "wet" purpura bleeding.
● Trauma, especially to the head.
● Exposure to antiplatelet medications (eg, aspirin, ibuprofen, other nonsteroidal
anti-inflammatory drugs [NSAIDs]) and anticoagulants (eg, heparin, warfarin).
Many children with ITP may have taken NSAIDs for a preceding viral illness.
Whether this increases bleeding risk is not clear.

Intracranial hemorrhage — ICH is the most serious consequence of

thrombocytopenia but is fortunately a rare complication of ITP in children, with
reported rates ranging from 0.1 to 0.8 percent [7,8,15,16,18-20]. This was illustrated
in reports of the Intercontinental Childhood ITP Study Group registry, which
reported 10 cases of ICH among 1784 patients (0.6 percent) [15], and from the
Nordic registry, which reported no case of ICH among 501 patients during the first
six months after diagnosis [18]. A systematic review of 51 prospective clinical trials
including 1965 children with ITP found that ICH occurred in 0.4 percent (95% CI 0.1-
0.9) [16]. More than 90 percent of ICHs in children with ITP are intraparenchymal
and supratentorial [21].

Children presenting with signs and symptoms concerning for ICH (eg, headache,
persistent vomiting, altered mental status, seizures, focal neurologic findings,
recent head trauma) require urgent evaluation (including neuroimaging) and
treatment. The threshold for obtaining neuroimaging in children with ITP is
substantially lower than for the general pediatric population, especially if the
platelet count is <10,000 to 20,000. (See "Immune thrombocytopenia (ITP) in
children: Management of newly diagnosed patients", section on 'Life-threatening
bleeding'.)

Risk factors for ICH are the same as for severe bleeding in general (ie, very low
platelet count, head trauma, exposure to antiplatelet medications, and signs of
excessive bleeding [eg, wet purpura in the mouth, hematuria, prolonged epistaxis,
GI bleeding, or other pronounced mucosal bleeding]) (see 'Serious hemorrhage'
above). Children who present with these risk factors should be carefully assessed
for signs or symptoms of ICH since the urgency and type of treatment will be
altered by presence of ICH. (See "Immune thrombocytopenia (ITP) in children:
Management of newly diagnosed patients", section on 'Life-threatening bleeding'.)

Laboratory findings — Thrombocytopenia usually is the only abnormality

detected. Other CBC parameters are generally normal, although there may be
exceptions ( table 4).
● Platelet count – A platelet count of <100,000/microL is used to define
thrombocytopenia in ITP [1]. However, in most case series, the presenting
platelet count is <30,000/microL [9,18]. This is probably because patients with
mild disease are less likely to have bleeding and may never come to medical
attention. Approximately 80 percent of children with ITP have platelet counts
<20,000/microL at presentation, and approximately 45 percent of children have
platelet counts <10,000/microL [8,15]. Platelet counts in children are generally
somewhat lower than in adults with ITP. Whenever possible, it is helpful to
determine if the patient has had a previously normal platelet count since this
helps to exclude an inherited thrombocytopenia. (See "Causes of
thrombocytopenia in children", section on 'Inherited platelet disorders'.)
● Other CBC findings – The white blood cell count and differential, hemoglobin
concentration, and other red cell indices are generally normal.

Anemia is occasionally seen in children with considerable ITP-related bleeding

(eg, epistaxis or heavy menstrual bleeding). The white blood cell count may be
modestly elevated or decreased if there has been an ongoing or recent
infection.

Pancytopenia or other abnormalities on the CBC that are not clearly explained
should prompt considerations of other etiologies. (See 'Differential diagnosis'
below.)
 ● Peripheral blood smear – On examination of the peripheral blood smear, the
white or red blood cells should generally appear normal. Exceptions to this
include patients with postinfectious ITP, in whom activated "atypical"
lymphocytes may be seen ( picture 3). However, distinguishing atypical
lymphocytes from lymphoblasts may be difficult. Patients with iron deficiency
anemia from excessive ITP-related bleeding may have microcytic hypochromic
red cells ( picture 4).

Platelets appear decreased in number but are usually normal or increased in

size, particularly if symptoms have been present for several days or longer.

Findings on peripheral smear that should prompt further evaluation include

(see 'Differential diagnosis' below and 'Further evaluation' below):

• Early white blood cell forms (eg, blasts) ( picture 5), suggesting leukemia or
lymphoma

• Polychromasia ( picture 6), reticulocytosis ( picture 7), and/or spherocytes

( picture 8), suggesting hemolytic anemia

• Schistocytes ( picture 9), suggesting microangiopathic hemolytic anemia

• Predominantly very large (giant) platelets ( picture 10) or predominantly

small platelets suggesting an inherited thrombocytopenia syndrome
( table 5A)

The approach to evaluating the peripheral blood smear is reviewed separately.

(See "Evaluation of the peripheral blood smear".)
● Bone marrow examination – Bone marrow examination (aspirate and biopsy)
is not routinely necessary for children with ITP unless atypical features are
present, as discussed below. (See 'Indications for bone marrow examination'
below.)

In patients with ITP, the bone marrow should be appropriately cellular and the
erythroid and myeloid precursors should be normal in number and
appearance. The megakaryocytes are typically normal or increased in number
and may appear large and/or immature [22].

EVALUATION
Initial evaluation — Initial laboratory testing for patients with suspected ITP
includes the following ( table 4) [23]:
● Complete blood count (CBC), including platelet count, white blood cell
differential, and red blood cell indices
● Examination of the peripheral blood smear

In addition, many experts (including the author of this topic review) often obtain
the following tests at the time of initial presentation:
● Reticulocyte count
● Direct antiglobulin test
● Serum immunoglobulin levels

The latter investigates the possibility of underlying common variable

immunodeficiency (CVID) [2]. (See 'Differential diagnosis' below and "Common
variable immunodeficiency in children".)

In some cases, it may be reasonable to include additional tests in the initial

laboratory panel (eg, antiphospholipid and antinuclear antibodies and thyroid
function tests to assess for autoimmune disorders in adolescent females).

Further evaluation — Consensus is lacking as to the extent of evaluation required

for the child with suspected ITP. For children with atypical findings (eg, systemic
signs and symptoms, other abnormalities in the CBC or peripheral blood smear)
( table 1), we suggest further investigation to evaluate for other possible causes
of thrombocytopenia ( table 6) [2]. The diagnostic evaluation should be directed
by a pediatric hematologist-oncologist aware of the subtleties to consider in the
evaluation.

Findings suggestive of other diagnoses — Additional testing should be

performed according to the reason for concern (see 'Differential diagnosis' below):
● Systemic signs and symptoms – Systemic signs and symptoms are typically
absent in ITP, with the exception of fatigue, which manifest as irritability in
infants and small children. Thus, other diagnoses should be considered in
children who have concerning systemic signs and symptoms (fevers, weight
loss, nonpetechial rash, joint pain, refusal to walk). These findings may indicate
the presence of a malignancy, autoimmune disorder, chronic infection, or
immune deficiency.
• Malignancy – Signs and symptoms concerning for malignancy include
lymph node enlargement, splenomegaly, bone or joint pain (especially if
bilateral and out of proportion to findings on examination), fevers, weight
loss, neutropenia, leukocytosis, or marked anemia. Although a single finding
in isolation does not always require evaluation for malignancy, a
combination of multiple findings (eg, pancytopenia; bone pain and
lymphadenopathy) is worrisome and generally warrants evaluation for
malignancy. In addition, certain findings are worrisome even as isolated
findings (eg, blasts on the peripheral blood smear) and require prompt
evaluation and consultation.

If there is sufficient clinical concern, evaluation for possible malignancy

should be performed, including bone marrow aspirate and biopsy and other
blood tests and imaging studies as appropriate. (See 'Indications for bone
marrow examination' below and "Overview of common presenting signs and
symptoms of childhood cancer".)

• Systemic illness or recurrent infection – Testing may also be warranted to

evaluate the following:
- Systemic lupus erythematosus (SLE) and other autoimmune disorders if
there is evidence of kidney disease, joint disease, antiphospholipid
antibodies, or other compatible findings. (See "Childhood-onset systemic
lupus erythematosus (cSLE): Clinical manifestations and diagnosis" and
"Antiphospholipid syndrome: Diagnosis" and "Autoimmune
lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)
- HIV, hepatitis C, cytomegalovirus, Epstein-Barr virus, Helicobacter pylori,
and possibly dengue and malaria (depending on travel history and
exposure). The evaluation for these is discussed separately. (See
"Screening and diagnostic testing for HIV infection in adults" and
"Hepatitis C virus infection in children" and "Overview of cytomegalovirus
infections in children" and "Laboratory tools for diagnosis of malaria".)
- Immune deficiency, especially CVID, Wiskott-Aldrich syndrome, and
DiGeorge syndrome. (See "Common variable immunodeficiency in
children" and "Wiskott-Aldrich syndrome" and "DiGeorge (22q11.2
deletion) syndrome: Clinical features and diagnosis".)
● Anemia – If there is evidence of hemolysis (eg, jaundice, elevated reticulocyte
count, abnormalities on peripheral smear [spherocytes, polychromasia,
schistocytes, elevated lactate dehydrogenase]), additional evaluation should be
performed.

• Evans syndrome – ITP associated with autoimmune hemolytic anemia

(AIHA) indicates a diagnosis of Evans syndrome. If there is evidence of
hemolysis and the direct antiglobulin test is strongly positive (confirming
Evans syndrome), testing for other autoimmune and immunodeficiency
disorders, including autoimmune lymphoproliferative syndrome (ALPS), SLE,
CVID, DiGeorge syndrome, and other immunodeficiency disorders, should
be pursued. (See "Autoimmune hemolytic anemia (AIHA) in children:
Classification, clinical features, and diagnosis", section on 'Evans syndrome'
and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features
and diagnosis".)

• Hemolytic uremic syndrome (HUS) – Hemolytic anemia and

thrombocytopenia following a recent history of diarrhea and gastroenteritis
warrants testing of kidney function (blood urea nitrogen, creatinine, and
urinalysis) and screening for Shiga toxin-producing bacteria to evaluate for
HUS. (See "Clinical manifestations and diagnosis of Shiga toxin-producing
Escherichia coli (STEC) hemolytic uremic syndrome in children".)

• Thrombotic thrombocytopenic purpura (TTP) – Inherited or acquired

causes of TTP or other thrombotic microangiopathies should be considered;
acquired TTP is typically a disorder of adolescents, but inherited TTP can
present at any age. TTP can result in life-threatening complications, and
delay in diagnosis and treatment may have serious consequences. (See
"Hereditary thrombotic thrombocytopenic purpura (hTTP)" and "Diagnosis of
immune TTP" and "Diagnostic approach to suspected TTP, HUS, or other
thrombotic microangiopathy (TMA)".)

• Non-hemolytic anemia in the absence of bleeding – In children with ITP

who present with concomitant non-hemolytic anemia (ie, low reticulocyte
count) that cannot be explained by bleeding, bone marrow aspirate and
biopsy are warranted to evaluate for malignancy and inherited or acquired
bone marrow failure syndromes. Inherited bone marrow failure syndromes
 may have associated physical findings (eg, short stature, hyper- or
hypopigmented skin lesions, and thumb and/or radial abnormalities in
Fanconi anemia). (See "Clinical manifestations and diagnosis of Fanconi
anemia", section on 'Clinical features' and "Treatment of acquired aplastic
anemia in children and adolescents" and "Overview of common presenting
signs and symptoms of childhood cancer".)
● Excessive bleeding – In patients with excessive bleeding (ie, greater than
expected based on platelet count and/or recurrent severe mucosal bleeding),
coagulation studies should be performed, including prothrombin time,
activated partial thromboplastin time, fibrinogen, and D-dimer. In addition,
screening for von Willebrand disease type 2B should be pursued since it is
associated with low platelets. Evaluation of platelet function can be considered,
though it may need to be deferred until the platelet count has recovered. (See
"Approach to the child with bleeding symptoms", section on 'Initial laboratory
evaluation'.)
● Concern for inherited thrombocytopenia – Evaluation for an inherited
thrombocytopenia ( table 5A-B) may be warranted in any of the following
scenarios:

• Review of the medical record reveals that the patient has had prior low
platelet counts (especially if there has never been a documented normal
platelet count)
• There is a family history of thrombocytopenia or any syndromic features
consistent with an inherited thrombocytopenic syndrome ( table 5A-B)
• Patient fails to respond to ITP treatment (if given) (see "Immune
thrombocytopenia (ITP) in children: Management of patients with persistent,
chronic, or refractory disease", section on 'Ongoing evaluation')

Inherited platelet disorders are discussed in greater detail separately. (See

"Causes of thrombocytopenia in children", section on 'Inherited platelet
disorders'.)

Indications for bone marrow examination — Bone marrow examination is not

routinely necessary for children with a typical presentation of ITP ( table 1)
[2,4,23]. It is performed in selected patients to exclude other causes of
thrombocytopenia, such as malignancy or bone marrow failure. Based on the
available data, treatment with glucocorticoids is not considered an indication for
bone marrow examination if the child otherwise has typical features of ITP [2,4];
however, expert opinion varies and some centers choose to perform a bone
marrow examination for all patients before initiating glucocorticoid treatment [24].
Other factors that may impact this decision include the experience of the clinician,
likelihood of repeated follow-up, and how the findings of the bone marrow
examination will alter management.

We generally perform bone marrow examination in the following patients [2,23]:

● Patients with atypical clinical or laboratory features at presentation that
suggest malignancy or bone marrow failure as discussed above (eg, especially
lymph node enlargement, splenomegaly, bone or joint pain, fevers, weight
loss, neutropenia, leukocytosis, atypical lymphocytes, or marked anemia). (See
'Findings suggestive of other diagnoses' above.)
● Patients with chronic ITP who have never had a documented robust response
to standard ITP treatments (eg, glucocorticoids, intravenous immune globulin
[IVIG], and/or anti-D immune globulin) demonstrating that the bone marrow is
intact. Our practice differs from the 2011 guidelines from the American Society
of Hematology, which state that bone marrow examination is not necessary in
children who fail IVIG [23]. This issue was not addressed in the 2019 American
Society of Hematology guidelines [25]. (See "Immune thrombocytopenia (ITP)
in children: Management of newly diagnosed patients", section on 'First-line
treatments'.)
● Patients who develop new findings during follow-up that are not consistent
with ITP (eg, subsequent clinical findings of lymph node enlargement;
organomegaly; bone or joint pain; fevers; or new laboratory findings of
neutropenia, leukocytosis, or anemia without bleeding) or who stop
responding to ITP therapies that had previously been effective.
● For the rare patient who has inadequate or transient response to ITP treatment
and is planned to undergo splenectomy, we suggest performing bone marrow
examination prior to surgery if it has not been performed previously. In the
contemporary era, splenectomy is rarely performed for management of ITP in
children and, when it is used, it is typically done only after the patient has failed
multiple other therapies [26]. Thus, most children will have undergone bone
 marrow evaluation prior to undergoing splenectomy. (See "Immune
thrombocytopenia (ITP) in children: Management of patients with persistent,
chronic, or refractory disease", section on 'Splenectomy'.)
● The rare patient with ITP that has not resolved by 12 months but who has
never required pharmacologic treatment and thus cannot be labeled as
responsive or refractory to treatment. Bone marrow examination may be
warranted in such patients to exclude other causes of persistent
thrombocytopenia since most children with moderate or mild ITP have
recovery of platelet counts within a year.

For children with a typical presentation and without any of the above concerns, the
likelihood of finding an alternative diagnosis on bone marrow examination appears
to be low. In a single-center retrospective study of 484 children who underwent
bone marrow aspiration to confirm a provisional diagnosis of ITP, none of those
with typical hematologic features of ITP (ie, normal white blood cell count and
hemoglobin) had evidence of leukemic changes or bone marrow failure, though
one patient was later diagnosed with aplastic anemia [27]. Among children with
nonspecific, "atypical" hematologic findings (n = 152), 7 percent were found to have
a diagnosis other than ITP, divided evenly between leukemia and bone marrow
failure. All of the children who were found to have other diagnoses had clinical
and/or laboratory findings at presentation that were suggestive of an alternative
diagnosis (eg, anemia, leukopenia, leukocytosis).

Similar findings were noted in another retrospective review of 127 children with
presumed ITP in whom bone marrow examination was performed [28]. Only five
patients (3.9 percent) had a diagnosis other than ITP. As in the previous study, all
presented with clinical and/or laboratory findings that were atypical for ITP.
Leukemia was not diagnosed in any patient.

In addition, childhood leukemia presenting as isolated thrombocytopenia has not

been reported in the centralized leukemia study registries, with the exception of a
single patient with Down syndrome who presented with isolated thrombocytopenia
and was found to have acute leukemia; however, this patient also had marked
splenomegaly.

Immature platelet fraction — The immature platelet fraction (IPF) is an

automated laboratory test used for quantifying platelet production and turnover.
The IPF assay uses nucleic acid-specific dyes to detect young platelets that contain
residual RNA (reticulated platelets). It is increasingly available on automated blood
cell counters. (See "Automated complete blood count (CBC)", section on 'Reticulated
platelets and immature platelet fraction (IPF)'.)

The utility of the IPF in evaluating children with suspected ITP is unclear. Some
experts have suggested that IPF might be useful in cases where the diagnosis of
ITP is uncertain, particularly to help distinguish ITP from bone marrow failure
states, including leukemia and acquired or inherited aplastic anemia. In our
experience, if the diagnosis of ITP is uncertain, bone marrow examination is the
most reliable and established method for excluding a diagnosis of leukemia or
aplastic anemia. However, the IPF may be helpful when used in conjunction with
other tests. (See 'Indications for bone marrow examination' above.)

Several studies have shown that IPF values are elevated in ITP and seem to be
higher than in bone marrow failure states [29-33]. However, whether IPF can
reliably distinguish between ITP and leukemia or bone marrow failure remains
uncertain. Some studies have suggested that IPF has prognostic value since high
IPF appears to be associated with better platelet function and lower bleeding risk
[31,33,34].

Additional clinical studies are needed to determine the role of IPF measurement in
the evaluation of children with ITP.

No role for antiplatelet antibody testing — Testing for antibodies to specific

platelet glycoproteins (GPs; such as GP Ib/IX) is not recommended for patients with
suspected ITP [2,4,23,35,36]. The presence of these antibodies does not exclude
thrombocytopenia due to other causes, nor does the absence of antibodies
eliminate the diagnosis of ITP. (See "Immune thrombocytopenia (ITP) in adults:
Clinical manifestations and diagnosis", section on 'Antiplatelet antibody testing'.)

DIAGNOSIS

ITP is largely a clinical diagnosis made in well-appearing patients with

mucocutaneous bleeding without other systemic signs or symptoms and with
laboratory confirmation of isolated thrombocytopenia. ITP is a diagnosis of
exclusion, so other causes of thrombocytopenia must be ruled out. In most cases,
the diagnosis can be established based upon the clinical presentation and results of
the initial laboratory evaluation ( table 4); however, in patients with atypical
findings, additional evaluation is warranted. (See 'Further evaluation' above.)

For children with a typical presentation of ITP (sudden onset of a petechial rash or
bruising in an otherwise well-appearing child), a presumptive diagnosis of ITP may
be established based upon all of the following criteria ( table 1) [1,4]:
● Platelet count <100,000/microL.
● Otherwise normal complete blood count (CBC) with normal differential white
count, hemoglobin, and reticulocyte count.
● No abnormalities on the peripheral blood smear. In particular, there should be
no evidence of hemolysis or blasts (atypical lymphocytes from viral activation
are acceptable although flow cytometry may be required to distinguish them
from leukemic blasts). (See "Approach to the child with lymphocytosis or
lymphocytopenia", section on 'Blood lymphocyte morphology'.)
● No findings on history and physical examination to suggest another cause of
thrombocytopenia. Children <1 or >10 years old should be scrutinized more
closely for any atypical features. Findings that suggest a diagnosis other than
ITP include:

• Systemic symptoms (eg, fever, anorexia, bone or joint pain, headaches, or

weight loss)
• History of clinically significant systemic disease
• Enlargement of lymph nodes, liver, or spleen
• Abnormal thumbs or forearms and/or hyper- or hypopigmented skin lesions
(suggestive of Fanconi anemia)
• Longstanding history of thrombocytopenia or atypical bleeding
• Family history of thrombocytopenia or bleeding of unknown etiology
In addition, an unequivocal response to standard ITP treatments (eg, intravenous
immune globulin [IVIG] and anti-D immune globulin), even if the response is
transient, helps to confirm the diagnosis. However, many patients do not require
such treatments. (See "Immune thrombocytopenia (ITP) in children: Management
of newly diagnosed patients".)

Distinguishing primary from secondary ITP may be difficult.

DIFFERENTIAL DIAGNOSIS

The diagnosis of ITP is generally straightforward in healthy-appearing children with

a typical presentation (ie, sudden onset of a petechial rash or bruising with isolated
thrombocytopenia on laboratory evaluation) ( table 1). However, in some cases,
other causes of thrombocytopenia must be excluded ( table 6). (See "Causes of
thrombocytopenia in children".)

Alternative diagnostic considerations include the following [2,22,37]:

● Leukemia – Acute lymphoblastic leukemia (ALL) is the most common
childhood leukemia. Children with ALL usually have other clinical and
laboratory findings that distinguish ALL from ITP. These include systemic
symptoms (eg, fever, bone and joint pain, or weight loss), hepatosplenomegaly,
lymphadenopathy, leukocytosis, and significant anemia (hemoglobin <10 g/dL).
The thrombocytopenia in ITP typically is more severe than in ALL. Examination
of the peripheral blood smear may demonstrate blast cells on the peripheral
blood smear, but these may be difficult to distinguish from atypical
lymphocytes that may be present in a postviral case of ITP. If there is concern
for leukemia, flow cytometry, molecular testing, and bone marrow examination
(aspirate and biopsy) should be performed. (See "Overview of the clinical
presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in
children".)
● Active infection – Ongoing viral infections, such as infectious mononucleosis
(Epstein-Barr virus), cytomegalovirus, hepatitis C, and HIV-1, can cause
thrombocytopenia. These disorders may be differentiated from ITP by the
presence of systemic signs and symptoms and by performing specific viral
testing [38]. (See "Clinical manifestations and treatment of Epstein-Barr virus
infection", section on 'Primary EBV infection in infants and children' and
"Overview of cytomegalovirus infections in children" and "Hepatitis C virus
infection in children" and "Pediatric HIV infection: Epidemiology, clinical
manifestations, and outcome".)
● Autoimmune hemolytic anemia (AIHA) – AIHA that occurs in combination
with thrombocytopenia is known as Evans syndrome. A hemolytic process is
suggested by the anemia, jaundice, elevated reticulocyte count, and
 spherocytes and polychromasia on the peripheral smear. The diagnosis of AIHA
is established by a positive direct antiglobulin test (formerly called the Coombs
test). If AIHA is diagnosed, testing for an underlying autoimmune disease or
immunodeficiency, including autoimmune lymphoproliferative syndrome
(ALPS) and common variable immunodeficiency (CVID), is important, as
discussed immediately below. (See "Autoimmune hemolytic anemia (AIHA) in
children: Classification, clinical features, and diagnosis".)
● Systemic autoimmune disease – Immune-mediated thrombocytopenia may
be the presenting manifestation of an autoimmune disease, such as systemic
lupus erythematosus (SLE) or ALPS. Autoimmune diseases are more common
in adolescent females.

• The most common initial symptoms of SLE are the gradual onset of fever,
malaise, and general deterioration over several months, with or without a
malar rash; joint stiffness consistent with mild arthritis may be the first sign.
Laboratory findings include the presence of autoantibodies, such as
antinuclear antibodies and antiphospholipid antibodies. (See "Childhood-
onset systemic lupus erythematosus (cSLE): Clinical manifestations and
diagnosis".)

• ALPS has been thought to typically present with chronic lymphadenopathy

and/or splenomegaly. However, it is now recognized that approximately one-
quarter of children presenting with Evans syndrome (even without
lymphadenopathy or splenomegaly) may actually have ALPS [39,40]. The
signature screening laboratory abnormality is increased numbers of
alpha/beta double-negative T cells detected by flow cytometric
immunophenotyping with triple color flow. (See "Autoimmune
lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)
● Immunodeficiency syndromes – Approximately 20 to 25 percent of patients
with CVID have associated autoimmune hematologic disorders, including ITP,
AIHA, or Evans syndrome [41]. Thus, patients with ITP and recurrent infections
should be evaluated for CVID and other immunodeficiency syndromes by
measuring serum immunoglobulin levels. Another characteristic of CVID-
associated ITP is recurrence. In our practice, we measure immunoglobulin
levels in all children with ITP because patients with CVID, especially those with
 autoimmune disease, often do not have a notable history of infections [2]. (See
"Common variable immunodeficiency in children".)

Wiskott-Aldrich syndrome should be considered in boys with eczema, small

platelet size, bleeding out of proportion to the platelet count, family history,
and/or lack of response to ITP treatments. DiGeorge syndrome should be
considered in patients with hypocalcemia and cardiac anomalies. (See "Wiskott-
Aldrich syndrome" and "DiGeorge (22q11.2 deletion) syndrome: Clinical
features and diagnosis".)
● Inherited disorders causing thrombocytopenia – Isolated thrombocytopenia
may be a presenting finding in certain rare inherited diseases, some of which
may also feature impaired platelet function ( table 5A-B). Some of these
syndromes are associated with other abnormalities (eg, immunodeficiency,
kidney disease, sensorineural hearing loss, risk of malignancy). Historical
platelet counts from children and their parents and ascertainment of the
duration of bleeding symptoms can help distinguish between congenital and
acquired causes. Inherited platelet disorders are discussed in greater detail
separately. (See "Causes of thrombocytopenia in children", section on
'Inherited platelet disorders'.)
● Drug exposure – Drugs commonly associated with thrombocytopenia include
heparin, quinidine, phenytoin, sulfonamides, valproate, and vancomycin;
others are summarized in the table ( table 2). This possibility is explored by a
history of exposure to such drugs, including whether the drugs are present in
the household and might have been accidentally ingested by the child. In a
child on such a medication, it should be changed to an equivalent medication,
if possible, to see if the "ITP" resolves. (See "Drug-induced immune
thrombocytopenia".)
● Bone marrow failure syndromes – In acquired bone marrow failure
syndromes (eg, aplastic anemia), a low platelet count is almost always
associated with other significant changes in the peripheral blood, such as
anemia, macrocytosis, low reticulocyte count, and/or leukopenia/neutropenia.
There may also be syndromic features. The diagnosis is established by bone
marrow examination including a biopsy and molecular testing and/or by
 genomic testing. (See "Treatment of acquired aplastic anemia in children and
adolescents".)
● Hemolytic uremic syndrome (HUS) – HUS is characterized by hemolytic
anemia, thrombocytopenia, and acute kidney injury. Patients may have a
history of gastrointestinal (GI) symptoms (bloody diarrhea, abdominal pain,
and vomiting) occurring approximately one week prior to the presentation of
HUS with transient resolution. HUS is distinguished from ITP on the basis of the
clinical history, presence of microangiopathic hemolytic anemia (with
fragmented erythrocytes [schistocytes] on peripheral smear ( picture 9)), and
abnormal kidney function (ie, oliguria, elevated blood urea nitrogen and
creatinine). (See "Overview of hemolytic uremic syndrome in children".)
● Thrombotic thrombocytopenic purpura (TTP) – TTP is characterized by
severe microangiopathic hemolytic anemia (with schistocytes on the peripheral
smear ( picture 9)), thrombocytopenia, fever, and neurologic abnormalities
(confusion, somnolence, headache). Kidney function impairment also may be
present, often with gross or microscopic blood in the urine and typically a very
high lactate dehydrogenase. TTP is associated with absent or reduced
ADAMTS13 activity: It can be hereditary or acquired. Graver systemic illness
suggests that ITP is not the diagnosis. (See "Diagnosis of immune TTP", section
on 'Clinical and laboratory findings' and "Hereditary thrombotic
thrombocytopenic purpura (hTTP)".)
● Disseminated intravascular coagulation (DIC) – DIC is characterized by
thrombocytopenia and a clinical picture of hemorrhage and thrombosis with
end-organ damage in the setting of an underlying condition such as sepsis,
trauma, or malignancy. The diagnosis of DIC is suggested by abnormal
coagulation studies (prothrombin time and activated partial thromboplastin
time), evidence of increased thrombin generation (ie, low fibrinogen), increased
fibrinolysis (eg, elevated D-dimer), and the presence of microangiopathic
changes on the peripheral blood smear (eg, schistocytes ( picture 9)). Patients
with DIC are usually considerably sicker than those with ITP, and often bleed
out of proportion to their already very low platelet counts. (See "Disseminated
intravascular coagulation in infants and children".)
SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links:
Immune thrombocytopenia (ITP) and other platelet disorders".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with
some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage
you to print or email these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the
keyword[s] of interest.)
● Basics topic (see "Patient education: Immune thrombocytopenia (ITP) (The
Basics)")

SUMMARY AND RECOMMENDATIONS

● Clinical presentation – The clinical features of childhood immune
thrombocytopenia (ITP) include the following ( table 1):

• Physical findings – The typical presentation is the sudden appearance of a

petechial rash, bruising, and/or bleeding in an otherwise healthy-appearing
child, with a peak in the three- to five-year-old age range. (See 'Clinical
features' above.)
 • Preceding viral illness or vaccination – Many children with ITP have a
history of preceding viral illness. ITP may also rarely occur following measles,
mumps, and rubella (MMR) vaccination. (See 'Preceding illness or
vaccination' above.)

• Absence of systemic symptoms – Other than mucocutaneous bleeding,

patients with ITP usually appear and feel well. The following features are
generally absent in children with ITP at onset of their disease (see 'Lack of
systemic signs and symptoms' above):
- Systemic symptoms (eg, fever, anorexia, bone or joint pain, weight loss,
or any other sign or symptom suggestive of an underlying serious
illness)
- Exposure to thrombocytopenia-inducing drugs ( table 2)
- Personal or family history of thrombocytopenia and/or bleeding
- Enlargement of lymph nodes, liver, or spleen on physical examination
If any of these features are present, other causes of thrombocytopenia
should be considered. (See 'Further evaluation' above.)
● Bleeding severity – Bleeding symptoms in children with ITP can range from
none or minimal (eg, few petechiae or small bruises) to, rarely, severe and life-
threatening (eg, intracranial hemorrhage [ICH], severe gastrointestinal [GI]
bleeding) ( table 3). Patients with platelet counts <10,000/microL are more
likely to have mucosal bleeding and ICH. (See 'Bleeding symptoms' above.)

• Mucocutaneous bleeding – Most patients have signs of cutaneous bleeding

(petechiae ( picture 2), purpura, and ecchymoses). Approximately 40
percent of patients also have mucosal bleeding (involving the nasal
passages, oral cavity, and genitourinary and GI tracts). (See 'Mucocutaneous
bleeding' above.)

• Serious and life-threatening hemorrhage – Serious hemorrhage requiring

hospitalization and/or blood transfusion occurs in approximately 3 percent
of children with ITP. ICH is the most severe consequence of ITP and occurs in
<1 percent of patients. (See 'Serious hemorrhage' above and 'Intracranial
hemorrhage' above.)
● Evaluation
 • Initial laboratory tests – We suggest the following initial laboratory tests
for the evaluation for patients with suspected ITP ( table 4) (see 'Initial
evaluation' above):
- Complete blood count (CBC) with differential and red blood cell indices
- Examination of the peripheral blood smear
- Reticulocyte count
- Blood type and direct antiglobulin test
- Immunoglobulin levels
In some cases, it may be reasonable to include additional tests in the initial
laboratory panel (eg, antiphospholipid antinuclear antibodies in adolescent
females).

• Additional evaluation – Evaluation for other causes of thrombocytopenia

should be carried out if there are findings that are inconsistent with ITP (eg,
abnormal white blood cell count or abnormalities on physical examination
or on peripheral blood smear) ( table 1). (See 'Further evaluation' above.)

A bone marrow examination is not routinely required in children with a

typical presentation and characteristic laboratory findings of ITP (ie, isolated
thrombocytopenia). Indications for bone marrow aspiration and biopsy
include atypical clinical or laboratory features at presentation, new findings
that emerge during follow-up that are not consistent with ITP, or failure to
respond to ITP treatment (if given). (See 'Indications for bone marrow
examination' above.)
● Diagnosis – ITP is largely a clinical diagnosis. For children with a typical
presentation of ITP ( table 1), the diagnosis of ITP is based upon the following
criteria (see 'Diagnosis' above):

• Platelet count <100,000/microL

• Otherwise normal CBC with normal differential white count, hemoglobin,
and reticulocyte count
• No abnormalities on the peripheral blood smear, particularly no evidence of
hemolysis or blasts
• No findings on history and physical examination to suggest another cause of
thrombocytopenia
 ● Differential diagnosis – Other causes of thrombocytopenia in children include
malignancy, infection, autoimmune disorders, immunodeficiency syndromes,
drug-induced thrombocytopenia, bone marrow failure, microangiopathic
hemolytic anemias (eg, hemolytic uremic syndrome [HUS], thrombotic
thrombocytopenic purpura, disseminated intravascular coagulation [DIC]), and
inherited thrombocytopenias ( table 6). (See 'Differential diagnosis' above and
"Causes of thrombocytopenia in children" and "Approach to the child with
unexplained thrombocytopenia".)
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