Immune thrombocytopenia (ITP) in children: Management of chronic disease

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Immune thrombocytopenia (ITP) in children:

Management of chronic disease
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: Oct 2023. | This topic last updated: Jul 14, 2022.

INTRODUCTION

Immune thrombocytopenia (ITP) of childhood is characterized by isolated thrombocytopenia

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

ITP in children often resolves spontaneously within three months. A minority of affected
children go on to have chronic ITP, which is defined as thrombocytopenia for >12 months
since presentation. (See "Immune thrombocytopenia (ITP) in children: Initial management",
section on 'Disease course'.)

The treatment and prognosis of chronic ITP and chronic refractory disease in children will be
reviewed here. The epidemiology, diagnosis, and initial management of ITP in children are
discussed separately. (See "Immune thrombocytopenia (ITP) in children: Clinical features and
diagnosis" and "Immune thrombocytopenia (ITP) in children: Initial management".)

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Immune thrombocytopenia (ITP) in children: Management of chronic disease

EPIDEMIOLOGY

Approximately 10 to 20 percent of children who present with ITP develop chronic ITP, defined
as platelet count <100,000/microL lasting beyond 12 months from the time of presentation [1-
6].

Risk factors — Chronic ITP cannot be predicted at diagnosis, but factors that correlate with
increased risk include [2,3,5]:

● Older age
● Higher presenting platelet count at initial diagnosis
● Insidious onset of symptoms
● Lack of preceding infection or vaccination prior to development of ITP
● Underlying chronic medical conditions (eg, autoimmune disorders)

This issue is discussed in greater detail separately. (See "Immune thrombocytopenia (ITP) in
children: Initial management", section on 'Disease course'.)

Genetic factors — Genetic factors may play a role in determining the risk of developing
chronic ITP. For example, studies have shown that certain polymorphisms in genes related to
immune function (eg, CD28, CTLA4, DNAM1, FCGR2B, ICOS, LAG3, PD1, TIM3, TLR4, TNFSF4)
may be associated with lower likelihood of responding to ITP therapies and/or increased
likelihood of developing chronic ITP [7-9]. Other studies have demonstrated potentially
pathogenic variants in immune-related genes (TNFRSF13B, CARD11, CBL, LRBA, NFKB2, RAG2)
in a subset of patients with chronic ITP, though most patients in these studies had other
subtle signs of primary immunodeficiency (eg, abnormal immunoglobulin levels, recurrent
infections) [10,11].

In addition, some patients labeled as having chronic refractory ITP may actually have an
inherited platelet disorder rather than an immune-mediated process. If possible, a previously
normal platelet count should be documented to exclude this possibility. Inherited platelet
disorders are discussed in greater detail separately. (See "Causes of thrombocytopenia in
children", section on 'Inherited platelet disorders' and "Inherited platelet function disorders
(IPFDs)".)
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Immune thrombocytopenia (ITP) in children: Management of chronic disease

EVALUATION

● Initial diagnostic evaluation – At the initial presentation of a child with symptoms

suggestive of ITP, a basic evaluation should be performed to exclude other causes of
thrombocytopenia. This includes a focused personal and family history, physical
examination, and laboratory testing, as summarized in the table ( table 1). A
previously normal platelet count should be documented whenever possible. Children
with atypical findings (eg, lymphadenopathy, splenomegaly, systemic symptoms, or any
abnormalities in the complete blood count (CBC) or peripheral blood smear) should
promptly undergo further investigation to exclude other causes of thrombocytopenia.
The initial diagnostic evaluation is discussed in detail in a separate topic review. (See
"Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on
'Diagnosis'.)

● Additional evaluation for children who develop chronic ITP – Additional evaluation is
performed both to exclude other causes of persistent thrombocytopenia (eg, bone
marrow failure, inherited thrombocytopenia) and to assess for underlying or secondary
causes of ITP such as immunodeficiency, chronic infection, or systemic
autoimmunity/inflammatory disorders ( table 2). (See "Immune thrombocytopenia
(ITP) in children: Clinical features and diagnosis", section on 'Differential diagnosis'.)

The approach to the evaluation for a child with chronic ITP is not standardized, and
practice varies regarding the specific tests performed. In our practice, we typically
perform the following tests at 6 to 12 months from diagnosis if ITP has not resolved:

• Serology and/or polymerase chain reaction testing for associated infectious causes
(human immunodeficiency virus [HIV], hepatitis C, cytomegalovirus, Helicobacter
pylori).

• Immunoglobulin levels and/or antibody response to routine childhood vaccines,

repeated annually for all children with chronic ITP. For children with additional clinical
concern for impaired immune function (eg, recurrent infections), additional testing
may be warranted, as discussed separately. (See "Approach to the child with

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Immune thrombocytopenia (ITP) in children: Management of chronic disease

recurrent infections".)

• Thyroid function tests, repeated annually.

• Studies to screen for systemic lupus erythematosus and other autoimmune disorders
(eg, antiphospholipid antibodies, antinuclear antibody test [and, if positive,
additional testing for specific autoantibodies]). (See "Measurement and clinical
significance of antinuclear antibodies", section on 'Indications for ordering
additional, specific tests for autoantibodies'.)

• In our practice, we perform bone marrow examination (including a biopsy,

cytogenetics, and fluorescence in situ hybridization) in most patients with chronic ITP
unless there is a documented robust response to intravenous immune globulin (IVIG)
or another ITP therapy demonstrating that the bone marrow is intact. Other experts
may not routinely perform bone marrow examination in this setting, particularly if
the child has a typical presentation and responds to ITP therapies.

GENERAL MEASURES

Supportive care — Supportive care for children with chronic ITP focuses on minimizing the
individual's risk for bleeding and alleviating other factors that may reduce quality of life, such
as fatigue and anxiety about bleeding risks. The components of supportive care are similar to
those for children with newly diagnosed or persistent ITP:

● If needed, restrict physical activities with significant risk of trauma, especially contact
and collision sports. The type of activity that is restricted has not been standardized, and
decisions should be individualized with participation of the patient and family. It is
important to not overly restrict participation in sports and other social activities.

● Avoid medications with antiplatelet activity, including ibuprofen and other nonsteroidal
antiinflammatory drugs, unless needed and tolerated; if used, the "acceptable" platelet
count level may need to be reset a little higher.

● Monitor menstrual bleeding and treat with hormonal therapy, antifibrinolytics, and/or

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Immune thrombocytopenia (ITP) in children: Management of chronic disease

iron supplementation if needed. (See 'Adjunctive therapies' below.)

● Monitor for epistaxis and treat with humidity, antiallergy measures, and antifibrinolytics
as needed. (See 'Adjunctive therapies' below.)

● Provide education to the child and caregivers about the risks and complications of ITP
and when to seek care. Information for patients and families/caregivers is provided
below (see 'Information for patients' below). Additional resources include the National
Institutes of Health website and the Platelet Disorder Support Association website.

Details of these supportive interventions are discussed in greater detail separately. (See
"Immune thrombocytopenia (ITP) in children: Initial management", section on 'General
measures'.)

Monitoring — The frequency of laboratory monitoring for patients with chronic ITP depends
on clinical symptoms, degree of the thrombocytopenia, treatment being used, and stability of
the platelet count. For example, if a previously asymptomatic patient develops new bleeding
symptoms requiring treatment, weekly monitoring with a complete blood count (CBC) is often
appropriate until the symptoms resolve and the platelet count stabilizes. If a patient has
minimal symptoms and the CBC is stable at a moderate degree of thrombocytopenia (50,000
to 100,000/microL), monitoring can be done less frequently (eg, once a month to every four
months). In our practice, we usually stop monitoring after the platelet count has returned to
normal and has remained stable for 6 to 12 months, though we may monitor it longer in
patients who had longstanding ITP before achieving normal counts.

Patients with chronic ITP also should be evaluated at least annually for thyroid disease
because of the high association between ITP and autoimmune thyroid disease [12]. In
addition, screening for common variable immunodeficiency with immunoglobulin levels
and/or antibody response to routine childhood vaccines should be performed annually. (See
"Acquired hypothyroidism in childhood and adolescence", section on 'Autoimmune thyroiditis'
and "Common variable immunodeficiency in children".)

MANAGEMENT

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Immune thrombocytopenia (ITP) in children: Management of chronic disease

Indications for treatment — Platelet counts can vary considerably in patients with chronic
ITP:

● Some patients maintain platelet counts between 50,000 to 100,000/microL without

treatment. Such patients generally do not experience bleeding symptoms and do not
require additional treatment unless a rise in platelet count is needed (eg, for surgery).

● Some patients remain relatively asymptomatic, but they may require occasional acute
intervention for management of intermittent episodes of clinically significant
thrombocytopenia, often triggered by an infection.

● Other patients may require continuous or intermittent therapy for management of

ongoing or recurrent bleeding symptoms or risks.

Thresholds for pharmacologic treatment depend on multiple factors, including ongoing

bleeding symptoms, risk factors for bleeding (sports or an active lifestyle), concomitant
medical conditions and medications, anxiety, fatigue, and access to medical care. Decisions
should be individualized and made in collaboration with the patient and family.

Children with chronic ITP should be managed by a pediatric hematologist whenever possible.
If regular visits to the hematologist are challenging for the family (eg, if it requires long-
distance travel back and forth to the specialty clinic), the primary care provider can provide
follow-up care in consultation with the hematologist. Virtual visits using telehealth are
another option.

Acute intervention for bleeding or risk of bleeding — The first-line pharmacologic options
for acute intervention are similar to those used in the initial management of patients with
newly diagnosed ITP and include intravenous immune globulin (IVIG), anti-D immune
globulin (anti-D), or glucocorticoids alone or in combination ( table 3). The dosing and
administration of IVIG and intravenous anti-D are the same as for initial management. (See
"Immune thrombocytopenia (ITP) in children: Initial management", section on 'First-line
therapies'.)

Infrequently, platelet transfusion(s) or combination therapy may be administered for life-

threatening bleeding or in the setting of major trauma. (See "Immune thrombocytopenia
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(ITP) in children: Initial management", section on 'Life-threatening bleeding'.)

Prolonged daily use of glucocorticoids should be avoided because of adverse effects,

especially on growth in children. (See "Major adverse effects of systemic glucocorticoids",
section on 'Young children'.)

Glucocorticoids may be appropriate if only infrequent short courses or pulses are required.
However, if repeated rescue treatment is required or ongoing treatment for more than a few
weeks is needed, we prefer steroid-sparing agents (eg, rituximab, thrombopoietic agents, or,
less commonly, azathioprine, 6-mercaptopurine [6-MP], mycophenolate mofetil [MMF],
sirolimus, or cyclosporine). (See 'Rituximab' below and 'Thrombopoietin receptor agonists'
below and 'Other agents' below.)

When an increased platelet count is needed for surgery or another activity with high risk of
bleeding, any first-line ITP therapy (glucocorticoids, IVIG, anti-D) may be used. Considerations
include the timing of surgery, the desired platelet count, and the patient's prior treatment
response. If there is sufficient time before surgery, short-term use of a thrombopoietin
receptor agonist (TPO-RA) may be useful as an adjuvant or an alternative to first-line agents.
However, there is a minimum of a five- to seven-day delay before a response is seen with TPO-
RAs, so they are not appropriate if an increased platelet count is needed more urgently. (See
'Thrombopoietin receptor agonists' below.)

Management of ITP in the setting of surgery and invasive procedures is discussed in greater
detail separately. (See "Immune thrombocytopenia (ITP) in children: Initial management",
section on 'Surgery/invasive procedures'.)

Ongoing management (second-line therapies)

Choice of therapy — For patients with chronic ITP whose symptoms and risks are not
adequately controlled using first-line therapies and for those who remain dependent on
glucocorticoid therapy to control symptoms, effective second-line treatment options include
rituximab, TPO-RAs (eltrombopag, romiplostim), and splenectomy. Other agents that are used
for patients who are treated by chronic immunosuppression include azathioprine, 6-MP, MMF,
sirolimus, and cyclosporine.

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In our practice, we most commonly use TPO-RAs for patients with ITP lasting ≥3 to 6 months
who require pharmacologic intervention, though there are exceptions (eg, rituximab is
preferred for patients with autoimmune disorders or autoantibodies). If the agent at maximal
dose for four weeks is ineffective, we consider adding an immunosuppressive agent (eg,
MMF).

However, the choice is complex and depends upon individual medical issues, past history,
family history, and values and preferences of the patient and family. It is important to
consider the following factors [13]:

● Age of the child – Splenectomy is rarely performed in children. In particular, it should

be avoided in young children (<5 years of age) and in those with immunodeficiency or
thrombotic tendency.

In adolescent females, we often use rituximab as the preferred agent for management
of chronic ITP. Our practice is based upon limited evidence suggesting that the response
to rituximab may be greater in adolescent females compared with young children and
males [14]. The reason is unclear but may be because the likelihood of an underlying
autoimmune disorder is higher in this population.

● Presence of other autoimmune disorders – Rituximab may be preferred over TPO-RAs

in patients with autoimmune disorders (eg, systemic lupus erythematosus, autoimmune
lymphoproliferative syndrome [ALPS]) since TPO-RAs do not have immunomodulatory
effects. Other immunosuppressive agents (eg, MMF, sirolimus) may also be considered
in these patients, particularly in patients with ALPS. (See 'Other agents' below and
"Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis".)

● Ease of administration – Eltrombopag is administered orally and may be preferred by

patients who wish to avoid infusions. However, some patients find it difficult to adhere
to the cumbersome dietary requirements for taking the drug as described below. (See
'Thrombopoietin receptor agonists' below.)

Oral immunosuppressive agents (eg, azathioprine, 6-MP, or MMF) are another option for
patients who wish to avoid more invasive therapies. However, the efficacy of these oral
immunosuppressive agents is not as well established and they all have potential for
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toxicity. These and other issues should be carefully discussed with the patient and
caregivers when selecting therapy. (See 'Other agents' below.)

● Expected adherence to treatment regimen – For patients with lower expected

adherence, rituximab or romiplostim may be preferred since these agents require less
day-to-day self-management. (See 'Rituximab' below and 'Thrombopoietin receptor
agonists' below.)

Splenectomy is another option for patients who cannot adhere to pharmacologic

therapy. However, as previously mentioned, splenectomy has substantial risks and
should be avoided in children <5 years old. (See 'Splenectomy' below.)

● Possibility of long-term remission – Most second-line agents do not achieve a durable

response over time. Among the various choices for second-line therapy, splenectomy
has the greatest likelihood of resulting in a sustained remission. However, splenectomy
is associated with substantial risks, including thrombosis and lifelong risk of
overwhelming sepsis. In addition, there is a greater tendency to spontaneous remission
in children with ITP compared with adults such that the temporary response from
pharmacologic therapy may be adequate to support the child until remission occurs
spontaneously. Thus, we generally reserve splenectomy for patients who have
persistent severe thrombocytopenia accompanied by clinically significant hemorrhagic
symptoms and who require repeated or continuous pharmacologic interventions. (See
'Splenectomy' below.)

In a study of 120 children with ITP (chronic or persistent ITP in most cases) managed at 21
centers from 2013 to 2015, the most commonly used second-line treatments were TPO-RAs
(17 percent) and rituximab (14 percent) [13]. Less commonly used treatments included 6-MP
(8 percent), splenectomy (5 percent), dapsone (4 percent), and MMF (3 percent). The most
commonly reported factors guiding treatment decisions were patient and parental
preference, side effect profile, possibility of long-term remission, and ease of administration.

Rituximab — Rituximab is a chimeric murine/human anti-CD20 monoclonal antibody that

targets autoantibody-producing B lymphocytes but not plasma cells [15,16]. Several
uncontrolled open-label studies support its use in pediatric patients with persistent or chronic

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ITP [17,18]. Randomized controlled trial data in pediatric patients are lacking. Indirect
evidence from clinical trials in adults with ITP is discussed separately. (See "Second-line and
subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'Rituximab'.)

Optimal dosing for rituximab in pediatric patients is not defined. The typical dose is 375
mg/m2 intravenously weekly for four weeks. We suggest glucocorticoid administration with
the first infusion to minimize acute reactions, especially fever and chills. A preparation of
rituximab for subcutaneous injection is also available. Biosimilars and second generation anti-
CD20 monoclonal antibody agents have been developed but have not been studied in
children with ITP [19].

Open-label studies in children with chronic ITP suggest an initial response rate of
approximately 40 to 50 percent, falling to approximately 25 percent over follow-up of two to
five years [17,18]. In a retrospective study of 33 children with chronic ITP who were treated
with four infusions of rituximab, 30 percent maintained a response at 60 months [14]. The
response rate in adolescent females (50 percent) was higher than in younger children and
males.

Mild, transient side effects may occur with the first infusion, including urticarial rash,
headache, fever, scratchy throat, and chills. Serum sickness occurs in 5 to 10 percent of
children with ITP treated with rituximab, a rate that is higher than in adults [18]. Progressive
multifocal leukoencephalopathy has been reported as a very rare but very serious
complication of rituximab therapy, including only one or two cases in a patient with ITP [20].
Pretreatment testing includes screening for hepatitis B carrier state and
hypogammaglobulinemia. Hepatitis B carriers may see activation with rituximab treatment.
Hypogammaglobulinemia, while infrequent with rituximab alone, may occur if rituximab is
administered concomitantly with dexamethasone and infrequently is severe enough to
require replacement [21]. Infrequently, B cell reconstitution may be delayed or incomplete
following rituximab treatment [22].

Thrombopoietin receptor agonists — TPO-RAs (eg, eltrombopag, romiplostim) are

emerging as effective agents for treatment of children with persistent and chronic ITP. These
drugs stimulate thrombopoiesis via the thrombopoietin receptor and are commonly used for
second-line treatment in adult patients with chronic ITP. (See "Second-line and subsequent
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therapies for immune thrombocytopenia (ITP) in adults", section on 'TPO receptor agonists'.)

TPO-RAs only support an increased platelet count as long as they are continued and have not
been shown to induce a lasting remission. However, since there is a greater tendency to
spontaneous remission in children with ITP compared with adults, the temporary response
may be adequate to support the child until remission occurs spontaneously. The routine use
of these agents may be limited by cost considerations.

Specific agents — Available TPO-RAs for use in children include eltrombopag and
romiplostim. Eltrombopag is given orally once daily, and romiplostim is administered as a
once-weekly subcutaneous injection. A third agent, avatrombopag, is approved for use in
adult patients.

● Eltrombopag – Eltrombopag is approved by the US Food and Drug Administration (FDA)

and the European Medicines Agency (EMA) for use in pediatric patients ≥1 year old with
chronic ITP refractory to other treatments [23]. The advantage of eltrombopag is that it
is administered orally. However, it requires that the child take the medicine on an empty
stomach without any intake within two hours before or after and without dairy (high
calcium or iron intake) for four hours before or after. This may be prohibitive for some
children.

The optimal dosing for eltrombopag is uncertain. The initial dose is typically based on
the age of the child [24]:

• Children 1 to 5 years – Initial dose is 25 mg orally once daily

• Children ≥6 years – Initial dose is 50 mg orally once daily

Dose reductions are necessary for patients with hepatic impairment and some patients
of Eastern Asian ancestry.

The dose is then adjusted in increments of 12.5 mg every two weeks (maximum dose 75
mg per day) as necessary according to the response. Liver function tests should be
monitored at least monthly during treatment.

Some children may require high doses. For example, in the clinical trial described below,

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many patients, particularly young children, required doses >2 to 3 mg/kg [24]. This is
considerably higher than the adult per kg dose (which is approximately 1 mg/kg). This
likely reflects accelerated metabolism and/or lesser sensitivity of marrow precursors to
eltrombopag in children compared with adults.

The efficacy and safety of eltrombopag in children has been investigated in two
randomized controlled trials, PETIT and PETIT2, which were the basis for the drug's
regulatory approvals for use in children [24,25]. In the larger trial (PETIT2), which
included 92 children with chronic ITP (duration >12 months), durable platelet response
(defined as platelet count ≥50,000/microL for six of eight weeks during the double-blind
period) occurred more frequently with eltrombopag than with placebo (40 versus 3
percent, respectively) and bleeding events were less common (37 versus 55 percent,
respectively) [24]. During the 24-week open-label treatment period that followed the
randomized trial, 81 percent of patients achieved at least one platelet count
>50,000/microL. Adverse events associated with eltrombopag were mild and included
transaminitis (3 percent of children had to discontinue eltrombopag because of
transaminitis) and minor respiratory symptoms. (See 'Adverse effects' below.)

Post-approval data on the experience using eltrombopag in the "real-world" setting (ie,
outside of a clinical trial) generally confirm the efficacy reported in the trials, with 60 to
75 percent of patients demonstrating a response to treatment [26,27]. In addition,
among patients using concomitant medications at time of starting eltrombopag, most
were able to reduce or discontinue concomitant medications after 6 to 12 months of
eltrombopag therapy.

Data on long-term use of eltrombopag in children remain very limited. (See 'Long-term
response' below.)

● Romiplostim – Romiplostim is administered weekly via subcutaneous injection. It is

approved by the FDA and EMA for use in pediatric patients ≥1 year old with chronic ITP
refractory to other medications [28,29]. Based on evidence from randomized clinical
trials and observational studies, the efficacy of romiplostim in children with chronic ITP
appears generally comparable to that of eltrombopag, though data directly comparing
the two agents are not available [30-37].
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The starting dose for romiplostim is 1 mcg/kg per dose given subcutaneously once
weekly. The dose is then adjusted in increments of 1 mcg/kg per week (maximum dose
10 mcg/kg per week) as needed according to the response.

The efficacy and safety of romiplostim in children was investigated in a multicenter

randomized trial involving 62 children with chronic ITP (duration >6 months) [37].
Durable platelet response (defined weekly platelet counts ≥50,000/microL without
rescue drug use in six of the final eight weeks of the six-month trial) occurred more
frequently with romiplostim compared with placebo (52 versus 10 percent, respectively).
Bleeding events, concomitant medication use, and use of rescue treatments were all
reduced by romiplostim. Treatment-related serious adverse events (which included
headache and thrombocytosis) occurred in one patient. Long-term use of romiplostim in
children suggests that platelet counts can be maintained for over four years with good
tolerability and without major toxicity similar to long-term data reported in adults [31].
Lack of response over time due to neutralizing antibodies has been reported and
appears to be more common in children compared with adults, though it is nevertheless
rare in both populations [36]. (See 'Long-term response' below.)

● Avatrombopag – In the United States, avatrombopag is approved for adults with ITP.
There are no available pediatric data, but a clinical trial is underway ( NCT04516967).
(See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in
adults", section on 'TPO receptor agonists'.)

Adverse effects — The available data suggest that eltrombopag and romiplostim are
generally safe and well tolerated in adults and children. In clinical trials, headache and mild
gastrointestinal complaints were the most commonly reported side effects.

Rare serious adverse events that can occur with either agent include thrombosis, bone
marrow reticulin fibrosis, and increased risk of myelodysplasia. The latter two in particular are
rare in primary ITP; their appearance suggests that the initial presentation might have truly
been a bone marrow disorder (eg, myelodysplastic syndrome) rather than ITP.

TPO-RAs may increase risks for thrombosis in patients with underlying risk factors for
thrombosis, but these issues are far less common in children than in adults. In a multicenter

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retrospective study of 79 children treated with TPO-RAs, pulmonary embolism (PE) occurred in
two patients (2.5 percent) [36]. Both patients had other underlying risk factors for thrombosis,
and neither had thrombocytosis at the time the PE developed.

Hepatic toxicity and cataracts have been reported with eltrombopag only [24,36,37]. However,
many patients undergoing treatment for chronic ITP have been exposed to steroids, which
can also cause cataracts. We do not routinely perform eye examinations if eltrombopag is
used, but we do ask about vision changes.

TPO-RA therapy appears to be associated with development of clinically mild reticulin fibrosis
over time. The clinical significance of this finding is uncertain, and there is no consensus on
monitoring. In one study, one-third of patients with this finding were noted to have had it
prior to or within several days of starting TPO-RA therapy [36].

Long-term response — Though the response to eltrombopag and romiplostim in the

clinical trials described above is promising, reports of the experience using these drugs in
clinical practice suggest that most children do not have a sustained response over time. In a
multicenter retrospective study of 79 children treated with TPO-RAs (43 with romiplostim, 28
treated with eltrombopag, and 8 with both agents), only 40 percent of patients demonstrated
a stable response over time [36]. An intermittent response requiring constant dose titration
was seen in 15 percent, and an initial response that waned to no response was seen in 13
percent. In one child, the lack of response was explained by the presence of a neutralizing
antibody to romiplostim. In the other cases, the cause for the waxing and waning response
was uncertain. Poor response to eltrombopag may be due to difficulties adhering to the strict
dietary requirements around taking the drug. Further exploration for loss of response to both
agents is ongoing.

Other agents — Additional immunosuppressive agents are frequently used in children with
late persistent or chronic disease. These include:

● Azathioprine [38,39]
● Cyclophosphamide [40]
● Cyclosporine [41-44]
● Danazol (after the child has entered puberty) [39]

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● Dapsone [45]
● Hydroxychloroquine [46]
● 6-MP [47]
● MMF [48,49]
● Sirolimus [50]

The most widely used agents are MMF, 6-MP, cyclosporine, and dapsone (the latter
predominantly outside of the United States). Sirolimus and hydroxychloroquine are also used
in specific circumstances (autoimmune lymphoproliferative syndrome, Evans syndrome,
positive antinuclear antibodies).

The use of these agents in childhood ITP is based on anecdotal clinical experience and small
clinical trials in adults. None of these agents have been demonstrated to have unequivocal
curative effects and all have some toxicity (hepatotoxicity, increased risk of infection). The rate
of efficacy of these agents is generally low. Nonetheless, these agents may have some utility
in certain refractory cases, alone or in combination with other agents. Combining
immunosuppressive agents increases efficacy but may also increase toxicity [51].

Splenectomy — In the modern era, splenectomy is very rarely used in the management of
pediatric ITP. It is an option for the small percentage of patients with chronic ITP who have
persistent clinically significant, generally severe thrombocytopenia accompanied by
hemorrhagic symptoms and require repeated or continuous pharmacologic interventions.
Although splenectomy is effective in most patients, it is also associated with substantial risks.
Rates of splenectomy among children with ITP have declined considerably since the early
2000s, likely due to increased availability of other effective second-line therapies [52]. (See
'Ongoing management (second-line therapies)' above.)

● Efficacy – Based upon observational data, splenectomy is effective (ie, it improves the
platelet count and reduces the associated risk of bleeding) in approximately 60 to 80
percent of children with chronic ITP [53].

● Risks – Splenectomy is associated with important risks, which must be weighed against
the benefits. The most critical is the small but lifelong risk of overwhelming infection,
which occurs in approximately 1 to 3 percent of splenectomized patients, usually with

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encapsulated organisms such as Pneumococcus, Haemophilus, and Neisseria. This risk

is highest in young patients (<5 years old) and those with underlying immune
dysfunctions (eg, ALPS) [54]. (See "Autoimmune lymphoproliferative syndrome (ALPS):
Management and prognosis", section on 'Avoidance of splenectomy'.)

The other major long-term risk associated with splenectomy is thrombosis, particularly
stroke. In a population-based study, splenectomized patients (mostly adults) had a 1.5-
fold increased risk of stroke compared with nonsplenectomized ITP controls [55]. In
addition, pulmonary hypertension has been observed in splenectomized patients with
hereditary spherocytosis but not in splenectomized ITP patients. (See "Hereditary
spherocytosis", section on 'Splenectomy'.)

● Evaluation prior to splenectomy – Prior to planned splenectomy, the diagnosis of ITP

should be critically reviewed to exclude causes of thrombocytopenia other than ITP,
especially those related to immune deficiency, ongoing viral infection, systemic
autoimmune disease (eg, systemic lupus erythematosus), bone marrow failure, or an
inherited form of thrombocytopenia ( table 2). This includes a comprehensive
serologic evaluation, as previously described. (See 'Evaluation' above and "Immune
thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on
'Differential diagnosis'.)

In addition, in our practice, in the rare instance when splenectomy is being considered
in a child with ITP, we perform a bone marrow examination prior to the procedure
unless there is a documented recent and robust response to IVIG or another ITP therapy
demonstrating that the bone marrow is intact. Our practice differs somewhat from the
2011 American Society of Hematology (ASH) guidelines, which state that splenectomy is
not necessarily an indication for bone marrow biopsy [56]. This guidance was not
revisited in the 2019 ASH guidelines [57].

● Immunizations and infection prevention – Presplenectomy immunizations are

necessary, and subsequent penicillin prophylaxis may be appropriate for all age groups.
These issues are discussed in detail in a separate topic review. (See "Prevention of
infection in patients with impaired splenic function".)

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Immune thrombocytopenia (ITP) in children: Management of chronic disease
● Monitoring after splenectomy – Platelet counts should be monitored for an indefinite
period following splenectomy until the count is clearly stabilized without additional
treatment. Once stabilized, the platelet count should be monitored at least yearly
depending upon whether the count remains low or has returned to normal.
Pneumococcal titers should be measured yearly as well to determine if additional
vaccination is warranted, though consensus is lacking as to the optimal frequency of
revaccination. (See "Prevention of infection in patients with impaired splenic function",
section on 'Vaccinations'.)

Patients with ongoing severe ITP after splenectomy and standard pharmacologic
therapies are considered to have chronic refractory ITP. Occasionally, an accessory
spleen causes late recurrence of ITP following splenectomy, especially if the initial
splenectomy resulted in remission for at least one year [58]. In such cases, the
possibility of an accessory spleen should be investigated with abdominal ultrasound or
computed tomography. This possibility is further suggested if Howell-Jolly bodies (
picture 1) are absent on the peripheral smear following splenectomy.

Adjunctive therapies — Adjunctive therapies may be used in the following settings to treat
or reduce the likelihood of clinically significant bleeding:

● Heavy menses – In patients with heavy menses, hormonal therapy may be helpful to
reduce bleeding. We generally use progesterone-based treatment (eg, 5 to 10 mg daily
of medroxyprogesterone acetate or depot medroxyprogesterone acetate) or a low-
estrogen formulation rather than a standard estrogen-based contraceptive. This is
because limited data suggest that progesterone may have positive effects on platelet
counts in ITP [59], while estrogen may promulgate autoimmunity [60]. Antifibrinolytic
agents (eg, epsilon aminocaproic acid or tranexamic acid) can also be used to treat
heavy menstrual bleeding, as discussed for mouth and nose bleeding below.

● Mouth and nose bleeding – Antifibrinolytic agents (eg, epsilon-aminocaproic acid or

tranexamic acid) can be used in children with significant mucosal bleeding, including
oral bleeding and epistaxis. Antifibrinolytic agents may also be used instead of or in
addition to measures to raise the platelet count prior to dental work. Intranasal DDAVP
(desmopressin) is another option for children with nose bleeding. Additional measures
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Immune thrombocytopenia (ITP) in children: Management of chronic disease

for nose bleeding include keeping the nasal mucosa moist (eg, with a humidifier or
saline nose spray), discouraging nose picking, and use of antiallergy remedies (if allergic
rhinitis is thought to be contributing). Ointments that require direct application are
generally not helpful, since the benefit of the ointment is offset by the trauma of the
application. Cautery may be useful but is rarely effective if used for a second time in the
same nostril and may damage the mucosa, paradoxically resulting in more bleeding.

Patients who have recurrent significant bleeding symptoms, including adolescent girls with
heavy menses, should be evaluated for iron deficiency, and iron supplementation should be
provided if warranted. (See "Iron requirements and iron deficiency in adolescents".)

PROGNOSIS

Spontaneous remission — Spontaneous remission occurs in up to 50 percent of children

after months or even years of chronic ITP; this is more common if the platelet count is not
very low. In a large registry study, more than one-quarter of those who still had ITP 12
months from diagnosis underwent complete remission by 24 months from diagnosis [6].
Similar outcomes were reported from a Nordic registry study of children with chronic ITP [5].
After two years of chronic ITP, 32 percent of subjects still had platelet counts that were
<20,000/microL, but 35 percent had recovered completely (platelets >150,000/microL). After
five years of chronic ITP, 12 percent of subjects had platelet counts <20,000/microL, while 52
percent had recovered completely.

Children <10 years old are more likely to enter remission than older patients [61,62]. Children
>10 years old, especially adolescent females, have a disease course more like that seen in
adults with ITP. Neither of these tendencies is enough to substantially alter management. The
role that hormonal and other physiologic changes of puberty play in this process is not well
understood. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on
'Disease course'.)

Bleeding risk — The risk of serious bleeding in chronic ITP is modest and depends largely
upon the platelet count. A very low count is permissive, but not sufficient, for bleeding. In the
Nordic registry study described above, <10 percent of patients with chronic ITP experienced a
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Immune thrombocytopenia (ITP) in children: Management of chronic disease

serious bleeding episode in five years of follow-up and, in each case, the bleeding episode
was in the context of a platelet count <20,000/microL [5]. The incidence of intracranial
hemorrhage is <1 percent but may be slightly higher among patients with chronic ITP as
compared with those with newly diagnosed ITP [63]. Patients with very low platelet counts
(eg, <10,000/microL) are at risk for serious bleeding even if they have not had previous
bleeding. Nearly all cases of intracranial hemorrhage occur at these very low counts.
However, there is individual variation in bleeding severity, which is not well understood and is
independent of the platelet count. This may be explained by differences in endothelial and
platelet function that are difficult to capture with available tests. (See "Immune
thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Intracranial
hemorrhage'.)

CHRONIC REFRACTORY IMMUNE THROMBOCYTOPENIA

Definition — Chronic refractory ITP is defined as refractory ITP after failure of splenectomy
and without lasting response to standard pharmacologic treatments, including
glucocorticoids, intravenous immune globulin, rituximab, and/or thrombopoietin receptor
agonists (TPO-RA). The primary criterion is failing to respond to splenectomy. However, this is
not a very useful criterion for pediatric patients since splenectomy is rarely performed for
management of ITP in children in contemporary practice, as discussed above (see
'Splenectomy' above). There may be a new definition promulgated in the future.

Evaluation — Patients with chronic refractory ITP may have underlying immune
dysregulation (eg, primary immunodeficiency, autoimmune disorder). Attempts should be
made to identify such conditions because, in certain cases, specific treatments may be
available. These conditions often have other characteristic findings (eg,
hypogammaglobulinemia). As previously discussed, patients should undergo periodic testing
of immunoglobulin levels, autoantibodies, and other tests to assess immune function as
appropriate based upon clinical findings. (See 'Evaluation' above.)

Evaluation for inherited thrombocytopenia (eg, with a selected gene panel) can also be useful.
A list of laboratories performing such testing is available on the Genetic Testing Registry.
(See "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders'.)
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Immune thrombocytopenia (ITP) in children: Management of chronic disease

In addition, patients with chronic refractory ITP who initially responded to splenectomy but
then relapsed in the first two years post-splenectomy should be evaluated for the possibility
of an accessory spleen.

Management — Chronic refractory ITP is rare in pediatric patients, and a standard approach
to its management is lacking. Agents that have been used for management of chronic
refractory ITP in childhood include azathioprine, 6-mercaptopurine (6-MP), cyclosporine,
dapsone, mycophenolate mofetil (MMF), and sirolimus. Additional agents that can be used
after the child enters puberty include danazol, hydroxychloroquine, cyclophosphamide, and,
potentially, fostamatinib (SYK inhibitor). As discussed above, the use of these agents is based
on anecdotal clinical experience in children and small clinical trials in adults. (See 'Other
agents' above and "Second-line and subsequent therapies for immune thrombocytopenia
(ITP) in adults".)

Many truly refractory patients are not responsive to single agents, and, therefore, using drug
combinations (especially agents with different mechanisms of effect and nonoverlapping
toxicities) is a strategy sometimes used in this setting. Combination therapy may achieve at
least a limited response using relatively low doses of individual agents, thereby avoiding
potential toxicity associated with very high doses. Effective combination regimens have not
been well defined or established. We generally include a TPO-RA agent as one of the
components.

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

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Immune thrombocytopenia (ITP) in children: Management of chronic disease

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 education" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Immune thrombocytopenia (ITP) (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Definition – Immune thrombocytopenia (ITP) is an immune-mediated process causing

low platelet count (<100,000/microL) without other hematologic abnormalities. Chronic
ITP is defined as ITP persisting beyond 12 months from the time of the initial
presentation of ITP. Approximately 10 to 20 percent of children with ITP develop chronic
ITP. Risk factors include adolescent age, less severe thrombocytopenia at the initial
diagnosis, insidious onset of symptoms, and underlying autoimmune disorders. (See
'Epidemiology' above.)

● Additional evaluation – Children who develop chronic ITP should have an additional
evaluation both to exclude other causes of persistent thrombocytopenia (eg, bone
marrow failure, inherited thrombocytopenia) and to assess for underlying or secondary
causes of ITP such as immunodeficiency, chronic infection, or systemic
autoimmunity/inflammatory disorders ( table 2). (See 'Evaluation' above and "Immune
thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on
'Differential diagnosis'.)

● General measures – Supportive care for children with chronic ITP typically involves (see
'Supportive care' above and "Immune thrombocytopenia (ITP) in children: Initial

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Immune thrombocytopenia (ITP) in children: Management of chronic disease

management", section on 'General measures'):

• Restriction of physical activities (eg, avoiding high-contact sports); however, it is

important to not overly restrict participation in sports or social activities
• Avoidance of medications with antiplatelet activity (especially nonsteroidal
antiinflammatory drugs)
• Regular laboratory monitoring
• Monitoring and/or treatment for heavy menstrual bleeding, epistaxis, and other
bleeding symptoms

● Factors determining need for treatment – The threshold for pharmacologic treatment
depends upon bleeding symptoms, risk factors for bleeding (eg, sports or an active
lifestyle), concomitant medical conditions and medications, anxiety, fatigue, and access
to and cost of medical care. Decisions should be individualized and made in
collaboration with the patient and family/caregivers. Children with chronic ITP should be
managed by a pediatric hematologist, if possible. (See 'Indications for treatment' above.)

● Acute intervention for bleeding or risk of bleeding – For children who require an
acute intervention to increase platelet count in the setting of an acute major bleeding
episode or surgery or in anticipation of an activity that increases risk for a bleeding
complication (eg, contact sport), the options for first-line pharmacologic treatment are
similar to those used for newly diagnosed ITP (these include intravenous immune
globulin [IVIG], anti-D immune globulin [anti-D], and glucocorticoids) ( table 3).
Prolonged daily use of glucocorticoids should be avoided because of adverse effects,
especially on growth in children. (See 'Acute intervention for bleeding or risk of bleeding'
above and "Immune thrombocytopenia (ITP) in children: Initial management", section
on 'First-line therapies'.)

● Patients who require ongoing therapy – For patients with chronic ITP whose
symptoms and risks are not adequately controlled using first-line therapies and for
those who remain dependent on glucocorticoid therapy to control symptoms, we
suggest treatment with either rituximab or a thrombopoietin receptor agonist
(eltrombopag, romiplostim) (Grade 2C). Other agents that are sometimes used for
patients who require chronic immunosuppression include azathioprine, 6-
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Immune thrombocytopenia (ITP) in children: Management of chronic disease

mercaptopurine (6-MP), or mycophenolate mofetil (MMF). The choice among these

options is complex and is highly dependent on the values and preferences of the patient
and family. (See 'Ongoing management (second-line therapies)' above and
'Splenectomy' above.)

● Prognosis – Spontaneous remission occurs within two years in approximately 30

percent of children with chronic ITP and by five years in approximately 50 percent of
affected children. Spontaneous remission is more common in younger children and if
the platelet count is not very low. Severe bleeding occurs in <10 percent of affected
children during five years of follow-up. (See 'Prognosis' above.)

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