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

Immune thrombocytopenia (ITP) in children: Management of chronic disease
Literature review current through: Jan 2024.
This topic last updated: Nov 27, 2023.

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".)

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)".)

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 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 'Follow-up evaluation'.)

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 [12].

Avoid medications with antiplatelet activity, including ibuprofen and other nonsteroidal antiinflammatory drugs (NSAIDs), unless necessary and the child has previously tolerated them. If NSAIDs or other antiplatelet medications are used frequently, it is reasonable to set a slightly higher goal for maintaining the platelet count.

Monitor menstrual bleeding and treat with hormonal therapy, antifibrinolytics, and/or 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 [13]. 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

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 higher 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 the burden of 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 (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, thrombopoietin receptor agonists [TPO-RAs]), 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 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.

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, we prefer rituximab 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 [14]:

Presence of other autoimmune disordersRituximab 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".)

Age and sex of the patient – 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 [15]. The reason is unclear but may be because the likelihood of an underlying autoimmune disorder is higher in this population. (See 'Rituximab' below.)

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. (See 'Splenectomy' below.)

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 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) [14]. 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 [16,17]. Several uncontrolled observational studies support its use in pediatric patients with persistent or chronic ITP [18,19]. Randomized controlled trial data in pediatric patients are lacking. Indirect evidence comes from clinical trials in adults with ITP, which are 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 [20].

Observational 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 [18,19]. 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 [15]. 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 [19]. 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 [21]. 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 [22]. Infrequently, B cell reconstitution may be delayed or incomplete following rituximab treatment [23].

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 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 [24]. 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 [25]:

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, many patients, particularly young children, required doses >2 to 3 mg/kg [25]. 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 [25,26]. 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) [25]. 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 [27,28]. 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 [29,30]. 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 [31-38].

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) [38]. 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 [32]. 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 [37]. (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 retrospective study of 79 children treated with TPO-RAs, pulmonary embolism (PE) occurred in two patients (2.5 percent) [37]. 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 [25,37,38]. 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 [37].

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 [37]. 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 [39,40]

Cyclophosphamide [41]

Cyclosporine [42-45]

Danazol (after the child has entered puberty) [40]

Dapsone [46]

Hydroxychloroquine [47]

6-MP [48]

MMF [49,50]

Sirolimus [51]

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 [52].

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 [53]. (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 [54].

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 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) [55]. (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 [56]. 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 [57]. This guidance was not revisited in the 2019 ASH guidelines [58].

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".)

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 [59]. 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 [60], while estrogen may promulgate autoimmunity [61]. 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 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 [62,63]. 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 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 [64]. 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'.)

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 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 management", section on 'General measures'):

Restricting physical activities (eg, avoiding high-contact sports); however, it is important to not overly restrict participation in sports or social activities

Avoiding 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 the burden of 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-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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