Immune thrombocytopenia (ITP) in children: Management of newly diagnosed patients

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, although it can be triggered by a viral or environmental trigger or it may be secondary to an underlying immunologic disorder [1-3]. ITP was previously known as idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura. The current term Immune ThrombocytoPenia preserves the widely-recognized acronym "ITP" and acknowledges the immune-mediated mechanism of the disorder, while allowing that patients may have little or no signs of purpura or bleeding [1].

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

TERMINOLOGY — 

The following terms are used in this topic:

●Primary ITP – ITP in the absence of other causes or disorders that are associated with immune-mediated thrombocytopenia is known as primary ITP and is the main focus of this topic review.

●Secondary ITP – Secondary ITP refers to immune-mediated thrombocytopenia with an underlying cause, including drug-induced, or associated with systemic illness (eg, systemic lupus erythematosus, common variable immunodeficiency, human immunodeficiency virus [HIV]). Secondary causes of immune-mediated thrombocytopenia are reviewed separately. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Differential diagnosis' and "Causes of thrombocytopenia in children", section on 'Immune-mediated causes'.)

Primary ITP is categorized into three phases, depending on the duration of the disease course [1]:

●Newly diagnosed ITP – ITP within 3 months from diagnosis

●Persistent ITP – Ongoing ITP between 3 and 12 months from initial diagnosis

●Chronic ITP – ITP lasting more than 12 months

In this terminology schema, there is no "acute" ITP. The clinical features of newly diagnosed, persistent, and chronic ITP are otherwise similar. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Clinical features' and 'Disease course' below.)

ITP can also be categorized according to the responsiveness to therapy, as discussed below. (See 'Refractory disease' below.)

Management of newly diagnosed ITP in children is reviewed here. The management of persistent and chronic ITP is discussed separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease".)

MANAGEMENT

General measures — We suggest the following measures for pediatric patients with ITP:

●Activity restriction – Affected children should be restricted from activities that carry a risk of bleeding from traumatic injury. The emphasis is on prevention of intracranial hemorrhage. There is no standard approach regarding the specific types of activity to restrict, and there is substantial variation in clinical practice. In general, there is arguably a tendency towards excessive restriction rather than too little. These decisions should be individualized and made in collaboration with the patient and family. In our practice, we advise that children with platelet count <30,000/microL avoid contact and collision sports (eg, football, boxing, lacrosse, and hockey) and also consider restricting other activities that have substantial risk for traumatic injury (eg, baseball, soccer, skiing, or gymnastics) [3]. Other experts use a higher threshold for participating in these activities (eg, a platelet count of 50,000 or 75,000/microL). For patients who elect to remain active in sports, certain modifications may be warranted (eg, wearing a helmet, avoid "heading" the ball in soccer). Protective helmets reduce but do not eliminate the risk of head injury.

●Avoidance of antiplatelet and anticoagulant medications – Antiplatelet medications (eg, aspirin, ibuprofen, other nonsteroidal anti-inflammatory drugs [NSAIDs]) and anticoagulants (eg, heparin, enoxaparin, warfarin, direct oral anticoagulants) generally should be avoided if the platelet count is <30,000/microL. In our experience, the risk of clinically significant bleeding with ibuprofen is low. Nevertheless, because of the potential for severe bleeding with its use, we advise avoiding ibuprofen unless it is absolutely necessary.

If these medications are necessary, pharmacologic treatment of the ITP may be warranted to increase the platelet count to a safe level (eg, for patients requiring ongoing anticoagulant therapy, the goal for platelet count is usually >50,000/microL). (See 'Moderate to high bleeding risk' below.)

For children with ITP who require antipyretic or analgesic therapy, we suggest starting with acetaminophen. If the child does not have adequate symptom relief with acetaminophen, other agents can be tried such as a cyclooxygenase-2 selective NSAID (eg, celecoxib) since these agents have less antiplatelet activity compared with ibuprofen and aspirin. However, a single dose of ibuprofen is unlikely to be harmful if the child does not have active bleeding. Other measures for pain not adequately controlled with acetaminophen include nonpharmacologic measures and/or opioids, if appropriate. These are discussed separately. (See "Pain in children: Approach to pain assessment and overview of management principles", section on 'Nonpharmacologic interventions' and "Pain in children: Approach to pain assessment and overview of management principles", section on 'Opioids'.)

●Monitoring – All patients should have ongoing monitoring for development of bleeding symptoms and regular measurements of platelet count, the frequency of which depends on the degree of thrombocytopenia, bleeding symptoms, and other risk factors. (See 'Monitoring' below.)

●Control of menses – For postmenarchal female patients, hormonal therapy may be warranted to control or inhibit menses and prevent severe menorrhagia. Antifibrinolytics may also be of use. These therapies are discussed in greater detail separately. (See "Anovulatory uterine bleeding in adolescents: Management" and "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Adjunctive therapies'.)

●Prevention and control of epistaxis – Measures to reduce the risk of epistaxis 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). For children who experience epistaxis, antifibrinolytics may be needed if bleeding is severe. These therapies are discussed in greater detail separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Adjunctive therapies' and "Management of epistaxis in children".)

●Education – Educating the child and caregivers about the risks of ITP is an important aspect of management. In addition to reviewing activity and medication management, as discussed above, the clinician should inform patients and caregivers at the time of diagnosis about symptoms of severe bleeding (eg, severe headache, hematuria, melena, heavy menstrual bleeding) and they should be instructed to consult their clinician if bleeding occurs. Information for patients and families/caregivers is provided below (see 'Information for patients' below). Additional resources include the Platelet Disorder Support Association website and the National Institutes of Health website.

Many of these warnings and precautions generally can be softened and ultimately lifted once ITP is controlled and the platelet count is recovering.

Treatment approach

Overview — Management of children with newly diagnosed ITP is based chiefly upon the severity of bleeding symptoms (table 1). Other risk factors (eg, degree of thrombocytopenia, the child's activity level), quality of life, and the values and preferences of the family/caregivers are also important considerations (algorithm 1).

Most patients with newly diagnosed ITP have mild or no bleeding symptoms. Children with no, mild, or low-risk moderate bleeding symptoms (grades 1, 2, or 3a on the modified Buchanan and Adix bleeding score (table 1)) can generally be managed with "watchful waiting" in the ambulatory setting, provided that the child is discharged to a reliable caregiver and follow-up is assured. Children with more serious bleeding symptoms (grades 3b and higher) require treatment [2,4,5].

The management approach described in the following sections is based upon the available evidence, expert opinion, and usual practice. Many of these considerations are reflected in an international consensus report and guidelines published by the American Society of Hematology [2,4]. Links to these and other society guidelines are provided separately. (See 'Society guideline links' below.)

Life-threatening bleeding — Life-threatening bleeding is rare in childhood ITP. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Serious hemorrhage'.)

If life-threatening hemorrhage occurs (eg, intracranial hemorrhage [ICH], major trauma, gastrointestinal bleeding with hemodynamic instability, pulmonary hemorrhage with cardiopulmonary compromise), immediate intervention is required. We recommend combination therapy with platelet transfusions, high-dose methylprednisolone, intravenous immune globulin (IVIG), and possibly intravenous (IV) anti-D immune globulin (anti-D) if the patient is eligible for anti-D [2].

●Platelet transfusions – In this setting, platelet transfusions are given as a bolus dose of 10 to 30 mL/kg, followed by a continuous infusion. The platelet count should be assessed immediately following the bolus (ie, 15 minutes after). Frequent testing thereafter is important to ensure that the patient maintains a hemostatic platelet count and to guide additional therapy. The goal is to maintain the platelet count >50,000/mL. Some advocate for maintaining the platelet count >100,000/mL in the setting of ICH, though this can be challenging to achieve in patients with ITP. Patients with ITP generally require larger-than-normal doses of platelets in transfusion due to rapid destruction. (See "Platelet transfusion: Indications, ordering, and associated risks".)

●Methylprednisolone – Methylprednisolone is given at a dose of 30 mg/kg per day (up to 1 g) intravenously (IV) for two to three days. (See 'Glucocorticoids' below.)

●IVIG – IVIG is given as a single dose of 1 g/kg. If needed (eg, if there is inadequate rise in the platelet count and ongoing concern for serious bleeding), the dose can be repeated once daily for a total of three days. (See 'Intravenous immune globulin' below.).

●Anti-D (if eligible) – IV anti-D can be added to the regimen in Rh-positive, direct antiglobulin test (DAT)-negative patients; however, the additional benefit of this agent in this setting is uncertain. IV anti-D is administered at a dose of 75 micrograms/kg as a single dose. IV anti-D can be a useful part of combination therapy, even in splenectomized patients despite its relative lack of efficacy when used as the sole agent in these patients [6]. Anti-D should not be given if the patient's DAT status is unknown, which is often the case in emergency situations. However, DAT testing is usually resulted quickly, so once the DAT status is confirmed to be negative and the blood type Rh+, IV anti-D can be given at the end of the IVIG infusion. (See 'Anti-D immune globulin' below.)

●Supportive critical care – Conventional critical care measures should be instituted for life-threatening bleeding, including transfusion of red blood cells, if appropriate, and surgical or endoscopic procedures to treat the bleeding site, if feasible. (See "Red blood cell transfusion in infants and children: Indications".)

For patients with severe ICH, interventions to reduce intracranial pressure (eg, mannitol, hypertonic saline, surgical intervention) may be warranted, as discussed separately. (See "Elevated intracranial pressure (ICP) in children: Management" and "Intracranial epidural hematoma in children", section on 'Surgical hematoma evacuation'.)

●Other adjunctive therapies – Additional interventions that have been used in patients with life-threatening bleeding but for which supporting evidence is limited include the following:

•Recombinant human factor VIIa. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Pediatric considerations'.)

•Antifibrinolytic agents (eg, epsilon aminocaproic acid, tranexamic acid) [7,8]. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Adjunctive therapies'.)

•Thrombopoietin receptor agonist (TPO-RA) – In most cases of life-threatening bleeding, we start TPO-RA agent in the early post-stabilization period. We usually use subcutaneous romiplostim since the acutely ill patient is unlikely to tolerate oral medications. The appropriate dose of romiplostim in this setting is undefined; we typically use the highest dose (ie, 10 mcg/kg). The TPO-RA agent has little impact on the acute bleeding event (there typically is a five- to seven-day delay before a response is seen); however, it may boost and prolong the platelet response in the days following the bleeding event, which may reduce the risk of rebleeding. This practice is not standardized, and other experts may choose not to use romiplostim in this setting. Additional details about TPO-RAs are provided separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Thrombopoietin receptor agonists'.)

•Vincristine [9]. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Other therapies and multi-agent combinations'.)

•Splenectomy – Emergency splenectomy may be lifesaving for patients with catastrophic bleeding that is refractory to medical management but should be considered as a last resort. Splenectomy may be challenging to perform in patients with active hemorrhage, who are inherently unstable, and should be performed by an experienced surgeon. The time required to arrange splenectomy may reduce the desired (urgent) effect. In one series of 40 children with ITP who suffered an ICH, splenectomized patients had worse outcomes, but this was likely due to confounding since more severely affected patients were more likely to undergo splenectomy [10]. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Splenectomy'.)

●Rationale for combination therapy – Combination treatment is generally more effective for immediately raising the platelet count compared with single-agent therapy [6]. Less intensive combination therapy may be used if there is potential for life-threatening bleeding but the circumstances are not imminently life-threating (eg, heavy gastrointestinal, genitourinary, or gynecologic bleeding; significant head trauma or severe unexplained headache without evidence of ICH). (See 'Severe, non-life-threatening bleeding' below.)

Severe, non-life-threatening bleeding — For severe mucosal bleeding or suspected internal hemorrhage that requires immediate medical attention but that is not life-threatening (eg, gastrointestinal bleeding without hemodynamic instability, pulmonary hemorrhage without cardiopulmonary compromise, severe prolonged epistaxis, muscle or joint hemorrhage), therapy is similar to that described above for life-threatening bleeding, with the following modifications:

●Platelet transfusions may not be needed – Platelet transfusions are generally reserved for patients with active life-threatening hemorrhage. However, platelet transfusions may be necessary for patients with non-life-threatening bleeding who do not achieve an adequate response with other treatments (eg, if the response is too slow or if the platelet count does not increase to an acceptable level) and those who require surgery. (See 'Surgery/invasive procedures' below.)

If platelet transfusions are used for any surgery other than splenectomy for ITP, one or more other therapies of ITP as described below should be instituted to further support the patient's postoperative platelet count since the transfused platelets would likely have a short half-life.

●Less intensive combination therapy – Rather than giving all three agents (methylprednisolone, IVIG, and IV anti-D) for up to three days, a measured approach using one or two of these agents for fewer days may be sufficient. The choice of agents can be guided by the patient's previous treatment response, if such experience exists. The choice and duration of therapy can be modified depending upon the response to treatment (ie, amelioration of bleeding and rise in platelet count).

As with life-threatening bleeding, we often administer a TPO-RA (eg, romiplostim [given subcutaneously] or eltrombopag [given orally]) to increase the likelihood of a higher platelet response. This practice is based on clinical experience and indirect evidence from other settings (eg, chronic ITP). These agents are discussed in greater detail separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Thrombopoietin receptor agonists'.)

Adjunctive antifibrinolytic agents (eg, epsilon aminocaproic acid or tranexamic acid) may be helpful in patients with severe bleeding, although data are limited and increased risk of thrombosis has been reported [7,8,11]. In addition, for patients with menorrhagia, hormonal therapy may be warranted. These interventions are discussed in greater detail separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Adjunctive therapies' and "Anovulatory uterine bleeding in adolescents: Management", section on 'Management of severe anovulatory uterine bleeding'.)

Moderate to high bleeding risk — For patients who currently lack evidence of severe bleeding, but who are deemed to be at moderate to high risk for bleeding complications, we suggest pharmacologic treatment.

●Definition of "moderate to high bleeding risk" – The risk of developing serious bleeding complications depends on the degree of thrombocytopenia, severity of bleeding symptoms (table 1), and additional risk factors. Though consensus is lacking and treatment is individualized, we generally define moderate to high bleeding risk as any of the following:

•Grade 3b bleeding symptoms (table 1)

•Planned surgery or invasive procedure that is likely to induce blood loss (see 'Surgery/invasive procedures' below)

•Platelet count <30,000/microL, plus one or more of the following risk factors:

-Concomitant use of anticoagulant or antiplatelet medications that cannot be discontinued

-Concomitant bleeding disorder (eg, von Willebrand disease)

-Very active lifestyle subjecting the patient to frequent trauma (that cannot be controlled with activity restriction) (see 'General measures' above)

-Close follow-up and/or other required parental/caregiver supervision cannot be assured or access to medical care is limited

●Choice of initial therapy – The choice of initial ITP treatment (eg, glucocorticoid, IVIG, and/or anti-D) depends in part on how rapid an increase in platelet count is desired:

•Rapid rise in platelet count is desired – When a rapid rise in platelet count is desired, we suggest treatment with IVIG or anti-D (the latter is used only in Rh-positive, DAT-negative, non-splenectomized patients without evidence of hemolysis) (table 2). (See 'Intravenous immune globulin' below and 'Anti-D immune globulin' below.)

Examples of circumstances wherein a rapid rise in platelet count may be desired include:

-Planned surgery or procedure that is likely to induce blood loss – Management of ITP in the setting of surgery and invasive procedures is discussed in greater detail below. (See 'Surgery/invasive procedures' below.)

-A child presenting after sustaining head trauma without evidence of ICH (however, if there is clinical concern for ICH following head trauma, more intensive therapy is warranted, as discussed above). (See 'Severe, non-life-threatening bleeding' above.)

-A child presenting with severe unexplained headache.

IVIG and anti-D are the preferred first-line therapies in these settings because they increase the platelet count more rapidly than glucocorticoids alone [12]. An increase in the platelet count is usually observed within 24 hours of administration of either agent.

•Rapid or urgent increase is not necessary – For patients with moderate to high bleeding risk in whom a rapid rise in platelet count is not necessary, we suggest initial treatment with oral glucocorticoids (eg, prednisone or dexamethasone) (table 2) [4]. (See 'Glucocorticoids' below.)

The preference for oral glucocorticoids in this setting is largely based on cost considerations and ease of administration. The choice of agent is also influenced by patient values and preferences, as well as the provider's experience with the agent. IV glucocorticoids, IVIG, and anti-D are reasonable alternatives. A TPO-RA agent may be reasonable in a select subset of newly diagnosed patients (ie, those who are likely to need prolonged support of the platelet count and who have recently used or are currently taking glucocorticoids [eg, for management of an underlying autoimmune disorder such as systemic lupus erythematosus or autoimmune lymphoproliferative syndrome]). TPO-RAs are discussed separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Thrombopoietin receptor agonists'.)

●Rationale for treatment – Patients with mucosal bleeding (ie, grade 3b on the on the modified Buchanan and Adix bleeding score (table 1)) at presentation are at increased risk of experiencing subsequent severe bleeding episodes [5,13]. This was demonstrated in a clinical trial involving 200 children with newly diagnosed ITP who were randomly assigned to early treatment with a single dose of IVIG or careful observation with treatment only in the case of severe bleeding [5]. For children with mucosal bleeding at presentation (n = 80), the rate of severe bleeding episodes during the first month was higher in the observation group compared with the IVIG group (17 versus 0 percent, respectively). For children with only mild bleeding symptoms at presentation, the rate of severe bleeding episodes during the first month was very low in both groups (2 and 0 percent).

Some patients with the above risk factors may not respond to standard treatment and may require either more aggressive treatment (eg, combination therapy) or early use of a second-line agent, as described below [6,10,12]. (See 'Response to treatment' below.)

Patients without any of the above risk factors generally do not require pharmacologic intervention and can be managed with "watchful waiting." (See 'Low bleeding risk' below.)

Low bleeding risk — Children with no bleeding, mild bleeding, or low-risk moderate bleeding (ie, grade 0 to 3a on the modified Buchanan and Adix bleeding score (table 1)) without any of the risk factors or circumstances described above generally do not require pharmacologic intervention and can be managed with "watchful waiting."

Arguments in favor of "watchful waiting" without early pharmacologic intervention are based upon the following observations:

●The available therapies (IVIG, anti-D, and glucocorticoids) are not curative. Approximately 50 to 70 percent of children recover from ITP within three to six months of presentation, with or without treatment [5,14,15]. Younger children and those with abrupt onset of bleeding symptoms have the greatest likelihood of recovering spontaneously [16,17]. (See 'Disease course' below.)

●Serious bleeding is uncommon in children who initially present with no or mild bleeding symptoms (ie, grade 0 to 3a). (See 'Disease course' below and "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Serious hemorrhage'.)

●Pharmacologic interventions for ITP all have potential for adverse effects.

Though we suggest an approach of "watchful waiting" for most children with low bleeding risk, the decision should be made in collaboration with the family/caregivers. Some providers may offer treatment to children with low bleeding risk if there is a high degree of fear or anxiety in the patient or caregivers, if the family will not accept watchful waiting, or if reliable follow-up cannot be assured. This is particularly relevant for patients with very low platelet counts (ie, <10,000). For children with substantially impaired quality of life due to symptoms (especially fatigue), anxiety about bleeding risks, or for whom restriction of activity would be especially burdensome, pharmacologic therapy may be a reasonable option (after discussing with the patient and/or caregivers and carefully weighing the potential risks and benefits). Potential but unproven benefits of this approach include relaxing restrictions on activity, improving quality of life, and preventing sequelae from bleeding; however, these must be weighed against the risks of side effects from ITP medications. Treatment may reduce the psychological burden for the parents of children with ITP, as shown in a pilot study of children treated with a TPO-RA [18].

Surgery/invasive procedures — Platelet count thresholds for surgery or invasive procedures are higher than thresholds to prevent spontaneous bleeding. Typical thresholds for different types of invasive procedures are presented separately. It is important to recognize that these thresholds are approximations and have not been substantiated in prospective studies. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Preparation for an invasive procedure'.)

Any first-line ITP therapy (eg, glucocorticoids, IVIG, anti-D) may be used in this setting. Considerations include the timing of surgery, desired platelet count, and patient's prior treatment response (if such experience exists). Optimally, treatment is initiated two to three days prior to surgery to optimize the hemostatic effect. For urgent or emergency procedures, we suggest IVIG plus IV methylprednisolone. Platelet transfusions may be required in addition to pharmacologic therapy. Depending upon the patient's prior treatment history, a TPO-RA may be a useful adjuvant in this setting if it is important to maintain a higher platelet count for a period of time postoperatively. These agents may require a longer "run in" to find the optimal dose for the patient without overshooting. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Thrombopoietin receptor agonists'.)

For elective procedures, in most cases, properly timed medication (IVIG, TPO-RA, glucocorticoids) can be used to raise the platelet count to the desired target. We generally use the agent that has been effective for the patient previously. Many experts prefer IVIG or TPO-RA agents over glucocorticoids in this setting due to theoretical concerns about infection or impaired wound healing with glucocorticoids.

Platelet transfusions are only transiently effective in patients with ITP. Thus, if possible, the preferred approach is to provide pharmacologic treatment preoperatively to increase the patient's own platelet count. This generally achieves a higher platelet count and lasts longer. If platelet transfusion is necessary, a continuous infusion may be required to achieve a durable response. Depending upon the procedure, ITP therapies may be supplemented by another approach (ie, simultaneous use of antifibrinolytics).

Target platelet count — For patients who are managed with pharmacotherapy, treatment is aimed at increasing the platelet count above a threshold that stops bleeding or reduces the risk of serious bleeding. We use a target of ≥20,000 to 30,000/microL in most cases (except in the case of life-threatening bleeding or major surgery, for which higher platelet counts may be necessary). (See 'Life-threatening bleeding' above and 'Surgery/invasive procedures' above.)

ITP therapies are temporizing interventions intended for short-term use to expeditiously reduce risk of hemorrhage. The goal of these treatments is not to achieve a normal platelet count. In particular, long-term glucocorticoid use is virtually never indicated in children and other options should be pursued in patients requiring ongoing treatment longer than two to four weeks [4].

As previously discussed, target platelet counts for surgeries and invasive procedures are higher than thresholds to prevent spontaneous bleeding. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Preparation for an invasive procedure'.)

Monitoring — Monitoring of patients with ITP, regardless of whether managed with pharmacologic therapy or "watchful waiting," should include regular clinical assessments and measurement of the platelet count. The frequency of monitoring depends on disease severity and treatment as well as parental and patient reliability.

In our practice, for patients managed in the outpatient setting, we typically monitor platelet counts once weekly initially. Hospitalized patients typically require more frequent monitoring (once or twice daily initially). The interval between testing can be gradually increased as the clinical picture stabilizes and the patient/family become more comfortable with the diagnosis. When recovery of platelet counts is detected, the interval between visits may be further lengthened, but monitoring should continue until the platelet count has returned to normal (>150,000/microL) and is stable without treatment. This recovery occurs within one to three months after presentation in one-half of children with ITP and by six months in approximately 60 to 75 percent of children [14,15]. (See 'Disease course' below.)

In our practice, we stop monitoring after the platelet count has returned to normal and has remained stable for two to six months. After this type of stable remission, recurrence of ITP is rare, occurring in <5 percent of cases [19]. A few patients have well-compensated or recurrent chronic ITP, with platelet counts that are usually normal but intermittently punctuated by relapses triggered by infection.

Response to treatment

Expected response — Approximately 75 to 90 percent of patients respond to initial treatment with first-line therapies. The timing of the response is variable and depends on which agent is used (1 to 4 days for IVIG and IV anti-D, 3 to 14 days for oral glucocorticoids) (table 2) [2,20].

Genetic variations in the immunoglobulin G (IgG) Fc receptor IIb (FCGR2B) appear to influence the response to IVIG and the likelihood of achieving early complete remission [5,21]. Patients expressing the FCGR2B-2321 allele have a high likelihood of compete response, whereas patients who express homozygous FCGR2B-232T are less likely to respond. However, this finding has not been confirmed in other studies and this testing is rarely performed in routine clinical practice. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Genetic factors'.)

Poor response to initial therapy — For patients who do not have an adequate response to the initial treatment (ie, ongoing moderate or severe bleeding symptoms in the setting of persistent platelet count <20,000/microL), we generally change to another therapy or use a combination of therapies. For example, for a patient who did not initially respond well to oral glucocorticoids, we might add IVIG or a TPO-RA agent. (See 'Intravenous immune globulin' below and "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Thrombopoietin receptor agonists'.)

Refractory disease — Refractory ITP is variably defined. One proposed definition for refractoriness among patients with newly diagnosed ITP (ie, within three months from diagnosis) includes both of the following criteria [22]:

●Moderate to severe ITP (ie, platelet count <20,000/microL and requiring treatment according to the criteria outlined above) (see 'Treatment approach' above)

●No response to at least two first-line treatments given at standard doses (table 2)

Management of refractory disease includes:

●Early transition to a second-line agent – Second-line agents (TPO-RAs and rituximab) have traditionally been reserved for patients with persistent or chronic ITP, but increasingly, they are being used for patients with newly diagnosed ITP that is refractory to first-line therapies [22]. We typically use a TPO-RA agent in this setting, though rituximab may be preferred if there is evidence of an underlying autoimmune disorder. Additional details of second-line agents for treatment of ITP are provided separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Second-line agents'.)

●Evaluation for other causes of thrombocytopenia – Patients with refractory ITP should undergo a thorough evaluation aimed at identifying alternative causes of thrombocytopenia (eg, bone marrow failure, inherited thrombocytopenia) and to assess for underlying or secondary causes of ITP such as immunodeficiency, chronic infection, or systemic autoimmune/inflammatory disorders (table 3) [23]. The approach to the ongoing evaluation for patients with refractory ITP is generally the same as for patients with chronic ITP, as discussed separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Ongoing evaluation'.)

Management of chronic refractory ITP is discussed separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Chronic refractory ITP'.)

Relapses — Approximately one-third to one-half of patients who initially respond to treatment with first-line therapies experience recurrent severe thrombocytopenia after the therapeutic effects of these medications wane [2]. The approach to retreatment of such patients is not standardized. In our practice, we treat recurrences according to the same indications used for initial treatment. (See 'Treatment approach' above.)

If the patient initially had a good response to treatment and subsequently requires retreatment, we generally use the same agent (table 2), unless retreatment would result in exposing the child to frequent or prolonged courses of glucocorticoids.

It is reasonable to change agents in the following circumstances:

●Adverse reactions to treatment – We change agents in this setting only if there were problematic reactions to the treatment that cannot be easily ameliorated with enhanced premedication, slower infusion time, or changing the brand (as is sometimes helpful with IVIG). Infusions of anti-D should be spaced sufficiently far apart so that any anemia and reticulocytosis related to the previous anti-D treatment have resolved (typically a minimum of two to three weeks between treatments).

●Prolonged use of glucocorticoids – Long-term glucocorticoid use (ie, more than two to four weeks) should be avoided [4]. Other options should be pursued in patients requiring prolonged or frequent courses of glucocorticoids. (See 'Second-line therapies' below.)

After retreatment, the frequency of laboratory monitoring is individualized, depending on the patient's individual risk factors for relapse or bleeding.

Some patients require multiple courses of treatment before recovering. Others receive multiple courses of treatment with transient responses each time but do not achieve remission (ie, they develop persistent or chronic ITP). The treatment of chronic ITP is discussed in a separate topic review. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease".)

FIRST-LINE TREATMENTS — 

The following sections summarize the different first-line treatment options for childhood ITP (table 2). The approach to selecting among these is summarized in the figure (algorithm 1) and described above. (See 'Treatment approach' above.)

Watchful waiting — Children with no bleeding, mild bleeding, or low-risk moderate bleeding (ie, grade 0 to 3a on the modified Buchanan and Adix bleeding score (table 1)) can generally be managed with "watchful waiting," provided that the child is discharged to a reliable caregiver and follow-up is assured. Most children with ITP fall into this category. (See 'Low bleeding risk' above.)

Watchful waiting consists of activity restriction as appropriate, regular clinical assessments, and serial measurements of the platelet count. (See 'General measures' above and 'Monitoring' above.)

If the child develops more serious bleeding symptoms (grade 3b of higher (table 1)), treatment should be initiated as detailed above. (See 'Treatment approach' above.)

Pharmacologic therapy — When the decision is made to use pharmacologic therapy to acutely increase the platelet count, first-line treatment options include glucocorticoids, intravenous immune globulin (IVIG), and intravenous (IV) anti-D immune globulin (anti-D) (table 2) [2,24]. The duration of acute symptomatic thrombocytopenia is shortened and signs of bleeding reduced by any of these modalities compared with no treatment [25-36].

There is substantial practice variation regarding selection and dosing of these different therapies. Selection among the agents is based upon the patient's condition, cost, availability, and ease of administration [4,37]. The approach is detailed above. (See 'Treatment approach' above.)

Glucocorticoids are less costly, though the cost differential depends upon whether hospitalization is part of the management plan. In addition, some providers routinely perform a bone marrow examination before treating with glucocorticoids (though it is not our practice to do so in children with typical features of ITP (table 4)), which further increases the burdens and costs of this treatment pathway. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Indications for bone marrow examination'.)

Glucocorticoids — For pediatric patients requiring treatment for ITP, glucocorticoids are effective in increasing the platelet count and are appropriate first-line agents either as monotherapy (if the child lacks severe bleeding) or in combination with other agents (if the child has severe bleeding) [4].

Various dose regimens have been used, and there is insufficient evidence to determine if any approach is superior to the others [4]. Our practice is to administer glucocorticoids as a short course at a relatively high dose to try to minimize toxicity associated with long-term use and because of a potentially more rapid onset of action.

●Dose – The following glucocorticoid regimens are commonly used [4,25,35]:

•For children with critical or severe bleeding – Methylprednisolone 30 mg/kg (maximum 1000 mg per day) as a single daily IV dose for two to three days

•For children without severe bleeding:

-Prednisone 2 to 4 mg/kg per day (maximum 120 mg per day) orally for five to seven days, OR

-Dexamethasone 0.6 mg/kg per day (maximum 40 mg per day) for four days orally or IV

●Efficacy – The efficacy of glucocorticoids for treating pediatric ITP is supported by randomized trials demonstrating that they increase platelet counts more rapidly compared with placebo [4,25,29]. Although most patients respond to glucocorticoids, a drop in platelet count after discontinuing therapy is common, unless spontaneous remission has occurred in the interim. Additional treatment may be necessary if significant bleeding symptoms persist or recur, but ongoing or intermittent glucocorticoid therapy for more than two to four weeks is strongly discouraged [4]. (See 'Expected response' above.)

●Adverse effects – Side effects of glucocorticoids include behavioral and mood changes, sleep disturbance, hypertension, increased appetite, gastritis, and weight gain. Long-term treatment with glucocorticoids should be avoided in children due the adverse effects on growth, bone health, immune function, and vision. (See "Major adverse effects of systemic glucocorticoids".)

Alternative therapies such as IVIG, IV anti-D, or second-line agents (eg, rituximab, thrombopoietin receptor agonists [TPO-RAs]) should be used instead of glucocorticoids for children who require prolonged or repeated therapy. (See 'Intravenous immune globulin' below and 'Anti-D immune globulin' below and 'Second-line therapies' below.)

●Mechanism of action – Glucocorticoids are presumed to have rapid effects by reducing the reticuloendothelial system phagocytosis of antibody-coated platelets and improving vascular integrity [38-40]. They also have delayed effects by reducing production of antiplatelet antibodies.

Intravenous immune globulin — When a rapid rise in platelet count is desired, we suggest IVIG as a first-line choice.

●Dose – For treatment of ITP, the usual dose IVIG is 0.8 to 1 g/kg given as a single dose. The single-dose regimen is generally preferable to regimens in which smaller doses are given over multiple days (eg, 0.2 g/kg daily for four or five days) since the former approach results in a faster rise in platelet count [4,20,35].

For children with life-threatening bleeding, the higher end of the dose range (1 g/kg) should be used. If the platelet count is inadequate and there is ongoing concern for serious bleeding, the dose can be repeated once daily for a total of three days.

We do not routinely use doses >1 g/kg in non-life-threatening situations since the available evidence suggests that higher doses (eg, 2 g/kg) are not more effective than the usual 0.8 to 1 g/kg dose [41].

●Efficacy – IVIG therapy results in a faster rise in the platelet count compared with glucocorticoids or no treatment [20,35,36,42-44]. A rise in the platelet count is usually observed within 24 hours of administration. In a meta-analysis of six trials comparing IVIG versus glucocorticoid therapy in 401 children with ITP, more patients in the IVIG group had platelet counts >20,000/microL at 48 hours after starting treatment (82 versus 59 percent; relative risk [RR] 1.35, 95% CI 1.18-1.54) [20].

Early treatment with IVIG does not appear to reduce the likelihood of developing chronic ITP, although remission may be achieved sooner [5]. (See 'Disease course' below.)

●Adverse effects – Adverse reactions to IVIG are common. The risk of adverse reactions generally correlates with the dose of IVIG and the rate of infusion. Adverse effects may be lessened by administering IVIG in smaller doses over several days (eg, daily infusions for three to five days rather than one or two days). However, this results in a slower platelet rise, and it is more burdensome on the patient and the medical system.

Most reactions are mild to moderate, transient, reversible events such as headache, chills, or flushing. Serious adverse reactions (eg, anaphylaxis, aseptic meningitis, thromboembolic events, acute kidney injury, severe hemolysis) occur in 2 to 6 percent of patients [45]. Post-infusion headaches are common and can be severe, especially in patients with a history of migraine headaches. Other common side effects include fatigue, abdominal pain, and myalgia. Transient neutropenia (absolute neutrophil count <1500/microL) develops in up to 30 percent of patients [46], but this effect is very short-lived and in most cases is clinically insignificant. Adverse effects may be more pronounced in adolescent patients. Adverse effects of IVIG and strategies to reduce them are discussed in greater detail separately. (See "Intravenous immune globulin: Adverse effects".)

●Premedication – Premedication with acetaminophen and/or diphenhydramine may reduce side effects. Providing prehydration prior to the infusion may help to reduce headaches, although there are no data to support this practice. In addition, in our practice, we routinely premedicate with a single dose of IV methylprednisolone to reduce the risk of side effects, particularly headache. Other experts do not advocate premedicating with methylprednisolone. A meta-analysis of observational studies raised concerns that coadministration of methylprednisolone and IVIG may be associated with increased risk of developing chronic ITP, but this is unlikely to be a causal association [47]. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Premedication'.)

●Mechanism of action – The exact mechanism of action of IVIG is incompletely understood and is likely multifactorial. Several lines of evidence suggest that the rapid increase in platelet count results from slowing of platelet destruction by inhibition of phagocytosis. Exactly how this occurs is still unknown. One hypothesis is that IVIG inhibits phagocytosis by upregulating the inhibitory IgG Fc receptor IIB (FCGR2B). Studies in ITP in adults with inhibitors of FcRn suggest that this contributes to the IVIG effect by reducing the level of antiplatelet antibodies. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Mechanisms of action'.)

Anti-D immune globulin — Anti-D immune globulin (anti-D, WinRho, RhoGAM, Rho[D] immune globulin) is a reasonable alternative to IVIG for appropriately selected children with ITP.

●Contraindications – Anti-D should not be used in patients with any of the following [4,48]:

•Rh-negative blood type

•Prior splenectomy

•Clinically significant anemia with marked reticulocytosis (suggestive of hemolytic anemia)

•Positive direct antiglobulin test (DAT; also known as Coombs test), unless this result is attributable to recent administration of anti-D

•Underlying comorbidities such as kidney disease, cirrhosis, or acute febrile illness

●Pretreatment evaluation – Pretreatment laboratory testing should include the following to look for evidence of baseline hemolysis, kidney dysfunction, or hematuria [4,49]:

•Blood group typing and DAT – These should be performed, even if already known, because only Rh-positive patients are eligible for anti-D treatment.  

•Complete blood count (CBC).

•Blood urea nitrogen, creatinine, and urine analysis.

●Dose, administration, and monitoring – Our suggested dose for anti-D is 75 micrograms/kg (375 international units/kg) given as a single IV dose.

Patients should be monitored during and for eight hours after the infusion [50]. Urine dipstick or urinalysis should be performed every few hours to test for hemoglobinuria. If any reaction occurs, a follow-up CBC should be obtained.

●Efficacy – The available clinical trial data suggest that anti-D, when given at a dose of 75 micrograms/kg, has similar efficacy compared with IVIG [12]; although at lower doses, it appears to be slightly less effective for rapidly raising the platelet count [51]. In a meta-analysis of seven trials comparing anti-D and IVIG therapy in 450 children with newly diagnosed ITP, fewer patients in the anti-D group had platelet counts >20,000/microL at 24 to 72 hours after starting treatment (71 versus 85 percent; RR 0.85, 95% CI 0.77-0.94) [51]. However, most of the trials in the meta-analysis used a lower dose of anti-D (50 micrograms/kg); only two trials used a dose of 75 micrograms/kg. In one of the largest trials involving 105 children who were assigned to receive a single dose of either anti-D (75 micrograms/kg) or IVIG (0.8 g/kg), the response to therapy (defined as a platelet count >20,000/microL at 24 hours) was similar in both groups (72 and 77 percent, respectively) [12]. At seven days, the mean platelet count was higher in the anti-D group compared with IVIG (312 versus 195/microL).

●Advantages of anti-D – Anti-D has several advantages compared with IVIG:

•Somewhat lower risk of infusion-related side effects such as headache, fatigue, chills, and flushing [51].

•Reduced donor exposure.

•Anti-D can be infused rapidly (in minutes), as compared with the slower infusion time required for IVIG (hours). However, anti-D requires pretreatment laboratory testing and a period of eight hours of observation and monitoring after infusion.

•In the United States, it is often difficult to obtain same-day approval for outpatient IVIG and approval for anti-D may be easier.

●Adverse effects – Anti-D can cause infusion-related side effects (eg, flushing, chills), though these are generally less common and less severe that those associated with IVIG. In addition, anti-D can cause rare but serious adverse effects that occur primarily in patients with underlying comorbidities. These reactions consist of severe intravascular hemolysis (occurring in approximately 1 out of 1100 treatments) with the possibility of concomitant kidney failure, disseminated intravascular coagulation, and even death [49]. This phenomenon is thought to be mediated by profound cytokine release.

●Premedication – We routinely premedicate with a single dose of methylprednisolone to increase efficacy and reduce the risk of side effects and cytokine release. Others do not routinely premedicate with methylprednisolone.

●Mechanism of action – IV anti-D acts by coating red cells with antibodies so that they bind the Fc gamma receptors in the reticuloendothelial system, interfering with removal of antibody-coated platelets. Consistent with this mechanism, anti-D is only effective in patients with Rh-positive blood types because only their red cells can be coated with anti-D. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'IVIG dosing and administration'.)

SECOND-LINE THERAPIES — 

Second-line agents include:

●Thrombopoietin receptor agonists (TPO-RAs; eg, eltrombopag, romiplostim) (see "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Thrombopoietin receptor agonists')

●Rituximab (see "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Rituximab')

●Alternative immunosuppressive agents (eg, azathioprine, cyclosporine, 6-mercaptopurine, mycophenolate mofetil, sirolimus, vincristine) (see "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Other agents')

These agents traditionally have been reserved for patients with ITP lasting ≥3 to 6 months whose symptoms and risks are not adequately controlled using standard therapies. However, second-line therapies are increasingly used earlier in the treatment course, particularly in children who have persistent thrombocytopenia who remain dependent on glucocorticoid therapy to control symptoms. Second-line therapies are described in greater detail separately. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Second-line agents'.)

OUTCOME

Disease course — Most children with newly diagnosed ITP recover within three to six months of presentation, with or without treatment [14,15].

Approximately 10 to 20 percent of affected children go on to have chronic ITP, which is defined as thrombocytopenia for more than 12 months since presentation [1,5,14,52,53]. (See 'Terminology' above.)

●Risk factors for chronic ITP – Factors that appear to be associated with increased risk of developing chronic ITP include [14-17,21,47,54-56]:

•Older age

•Less severe thrombocytopenia at the initial diagnosis

•Insidious onset of symptoms

•Lack of preceding infection or vaccination prior to development of ITP

•Lack of mucosal bleeding at diagnosis

However, these findings do not reliably predict whether chronic ITP will develop in a specific patient. Other attempts to predict chronicity have suggested biologic markers, but none are conclusive or in routine use. In the setting of ITP and autoimmune hemolytic anemia (Evans syndrome), studies have identified underlying genetic abnormalities in 50 percent of cases.  

●Impact of pharmacologic therapy – Early pharmacologic intervention does not appear to reduce the likelihood of developing chronic ITP. This was demonstrated in a clinical trial in which 200 children with newly diagnosed ITP were randomly assigned to early treatment with a single dose of intravenous immune globulin (IVIG) or careful observation with treatment only in the case of severe bleeding [5]. Upfront treatment with IVIG led to faster recovery of platelet counts and fewer severe bleeding episodes (1 versus 9 percent); however, the rate of progression to chronic ITP (defined as ITP lasting >12 months) was similar in both groups (10 and 12 percent). Of note, most patients who experienced severe bleeding episodes in this trial had mucosal bleeding (ie, Grade 3b on the modified Buchanan and Adix bleeding score (table 1)) at presentation and thus would have received treatment according to our approach outlined above. (See 'Moderate to high bleeding risk' above.)

Earlier observational studies reported conflicting results with some showing an association between early treatment with IVIG and lower rates of chronic ITP [47,56,57], while others did not find any association between early treatment and subsequent development of chronic ITP [58].

Based on the available evidence, treatment should be directed at control of symptoms (ie, stopping severe hemorrhage, minimizing the risk of bleeding, and improving quality of life) rather than preventing development of chronic ITP. (See 'Treatment approach' above.)

Bleeding complications — Reported rates of serious bleeding in children with ITP range from 3 to 20 percent, depending on the criteria used to define severe bleeding the population studied (some studies included both patients with newly diagnosed and chronic ITP) [13,59,60]. In a large registry study of that included 863 children with newly diagnosed ITP, 4 percent of patients experienced a severe bleeding episode (defined as requiring hospital admission and/or blood transfusion) either at presentation or during the first four weeks after diagnosis.

The incidence of intracranial hemorrhage (ICH) in children with newly diagnosed ITP is approximately 0.5 percent [13,15,59,60].

Most serious bleeding episodes occur in patients with severe thrombocytopenia (ie, platelet count <20,000), especially those with a prior history of mucosal bleeding [5]. However, serious bleeding can occur with higher platelet counts and many children with severe thrombocytopenia never experience serious bleeding. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Serious hemorrhage'.)

In a registry study of 501 patients from the five Nordic countries, approximately 85 percent of patients had severe thrombocytopenia (platelet count <20,000/microL) at the time of presentation [15]. Approximately 60 percent of these patients received pharmacologic treatment (most commonly IVIG) within two weeks of diagnosis. Severe thrombocytopenia resolved within one month in 75 percent of patients and persisted for >6 months in 10 percent. There were 33 episodes of mucosal bleeding (epistaxis, oral bleeding, menorrhagia, or rectal bleeding), which mostly occurred in patients with severe thrombocytopenia; there were no episodes of life-threatening bleeding or ICH. Fifteen of the bleeding episodes required blood transfusion.

Mortality — Mortality is very rare in children with ITP. Mortality in newly diagnosed patients is almost entirely due to catastrophic bleeding complications, particularly ICH, whereas mortality and morbidity in patients with chronic ITP may also be due to infections as a complication of long-term immunosuppressive treatment.

In one study, children with ICH had a 25 percent mortality rate and 33 percent of the survivors had neurologic complications at median follow-up of 11 months [10]. Outcomes were somewhat better for patients whose ICH was precipitated by head trauma or who presented with ICH, compared with those who developed ICH after diagnosis of ITP.

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 5^th to 6^th 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 10^th to 12^th 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 e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

●Treatment approach – For children with newly diagnosed ITP, management is based chiefly upon the severity of bleeding symptoms (algorithm 1). Other risk factors (eg, degree of thrombocytopenia, the child's activity level), quality of life, and values and preferences of the family/caregivers are also important considerations. (See 'Treatment approach' above.)

•General measures – Management of pediatric patients with ITP includes activity restriction, avoidance of antiplatelet and anticoagulant medications, regular monitoring of platelet count, and monitoring for clinical bleeding. (See 'General measures' above and 'Monitoring' above.)

•Watchful waiting for most patients – For most children with no bleeding, mild bleeding, or low-risk moderate bleeding (ie, grade 0 to 3a on the modified Buchanan and Adix bleeding score (table 1)), we suggest watchful waiting rather than pharmacologic therapy (Grade 2C). Most children with ITP fall into this category. These patients are at low risk of experiencing serious bleeding complications and most will have spontaneous remission without treatment. (See 'Low bleeding risk' above.)

Watchful waiting consists of regular clinical assessments and serial measurements of the platelet count. If the child develops more serious bleeding symptoms (grade 3b of higher (table 1)), treatment should be initiated as described in the bullets below. (See 'Watchful waiting' above and 'Monitoring' above.)

Pharmacologic therapy is a reasonable alternative to watchful waiting for patients with impaired quality of life (eg, due to fatigue, anxiety about bleeding, or burdens of activity restriction) or if reliable follow-up cannot be assured. (See 'Pharmacologic therapy' above.)

•Moderate to high bleeding risk – For patients with moderate to high bleeding risk (ie, grade 3b on the modified Buchanan and Adix bleeding score (table 1) or one of the other risk factors listed in the algorithm (algorithm 1)), we suggest pharmacologic therapy rather than watchful waiting (Grade 2B). For most patients in this category, we suggest oral glucocorticoids (eg, prednisone or dexamethasone) as first-line agents (Grade 2C). Dosing is provided in the table (table 2). (See 'Moderate to high bleeding risk' above and 'Glucocorticoids' above.)

Exceptions to this include circumstances wherein a rapid rise in platelet count is desired (eg, patients undergoing surgery). In such cases, we suggest either intravenous immune globulin (IVIG) or intravenous (IV) anti-D immune globulin (anti-D, WinRho, RhoGAM, Rho[D] immune globulin) (Grade 2C). Anti-D should not be used in patients with Rh-negative blood type, positive direct antiglobulin test (DAT), hemolytic anemia, or prior splenectomy. (See 'Surgery/invasive procedures' above and 'Intravenous immune globulin' above and 'Anti-D immune globulin' above.)

•Severe and life-threatening bleeding  

-Combination therapy – For patients with severe or life-threatening bleeding (ie, grade 4 or 5 on the modified Buchanan and Adix bleeding score (table 1), we suggest combination therapy with both high-dose IV methylprednisolone and IVIG rather than either agent alone (Grade 2C). Dosing is provided in the table (table 2). (See 'Life-threatening bleeding' above and 'Severe, non-life-threatening bleeding' above and 'Glucocorticoids' above and 'Intravenous immune globulin' above.)

-Platelet transfusions – Patients with life-threatening bleeding require platelet transfusions, given as a bolus dose of 10 to 30 mL/kg, followed by a continuous infusion. Patients with ITP generally require larger-than-normal doses of platelets in transfusion due to rapid destruction. (See 'Life-threatening bleeding' above and "Platelet transfusion: Indications, ordering, and associated risks".)

-Other agents – For patients with life-threatening bleeding, we suggest adding IV anti-D to the regimen if the patient is Rh-positive and DAT-negative (Grade 2C); however, the additional benefit of anti-D in this setting is uncertain and practice varies. (See 'Anti-D immune globulin' above.)

In addition, we suggest a high dose of a thrombopoietin receptor agonist (TPO-RA; eg, romiplostim) (Grade 2C). Though this agent has little impact on the acute bleeding event, it may boost and prolong the platelet response in the days following the bleeding event. (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Thrombopoietin receptor agonists'.)

●Management of refractory ITP and relapses – For patients who do not have an adequate response to initial treatment (ie, ongoing moderate or severe bleeding symptoms in the setting of persistent thrombocytopenia), we generally change to another agent or use combination therapy. (See 'Poor response to initial therapy' above.)

We treat relapses according to the same indications used for initial treatment. If the patient initially had a good response and subsequently requires retreatment, we generally use the same agent unless retreatment would result in exposing the child to frequent or prolonged courses of glucocorticoids. (See 'Relapses' above.)

Second-line agents (eg, TPO-RAs [eltrombopag, romiplostim] or rituximab) are increasingly used earlier in the treatment course, particularly in children who have persistent thrombocytopenia and bleeding who would otherwise require frequent and/or prolonged glucocorticoid therapy to control symptoms. (See 'Refractory disease' above and "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease", section on 'Second-line agents'.)

●Disease course – Most children with ITP recover within three to six months of presentation, with or without treatment. Approximately 10 to 20 percent of affected children go on to have chronic ITP, which is defined as thrombocytopenia for >12 months since presentation. Risk factors for developing chronic ITP include older age, less severe thrombocytopenia at the initial diagnosis, insidious onset of symptoms, and lack of preceding infection or vaccination prior to development of ITP. Early pharmacologic intervention does not appear to reduce the likelihood of developing chronic ITP. (See 'Disease course' above.)