Immune Thrombocytopenia (ITP) Guidelines

In 2019, the American Society of Hematology (ASH) published an update to its 2011 evidence-based practice guideline for immune thrombocytopenia (ITP). The 2019 guideline comprises strong recommendations and conditional recommendations/suggestions. Recommendations and suggestions are provided separately for pediatric and adult patients. Some of the 2011 recommendations remain unchanged and were not included in the 2019 review and update. ^[8]  In 2013, ASH issued a clinical practice guide on the treatment of thrombocytopenia in pregnancy, based in part on the 2011 guideline. ^{[18, 57]}

In 2019, an international group of experts published an International Consensus Report on the investigation and management of primary immune thrombocytopenia, covering adult, pediatric, obstetric, neonatal, and emergency management. The report updates an earlier guideline published in 2010. ^[46]

Pediatric ITP

Diagnosis

ASH recommendations are that bone marrow examination is not necessary in children and adolescents with the typical features of ITP, or in children in whom intravenous immunoglobulin (IVIG) therapy fails. ASH suggests that bone marrow examination is not necessary in similar patients before initiation of treatment with corticosteroids or before splenectomy, and that testing for antinuclear antibodies is not necessary in the evaluation of children and adolescents with suspected ITP. ^[57]

Treatment

ASH has moved away from recommending treatment on the basis of the platelet count. The 2019 ASH guidelines recommend that children with no bleeding or mild bleeding (ie, skin manifestations only, such as bruising and petechiae) be managed with observation alone regardless of platelet count. ^[8]

ASH suggestions include the following for children with non–life-threatening mucosal bleeding and/or diminished health-related quality of life (HRQoL) ^[8] :

• A short course of corticosteroids over anti-D immunoglobulin or IVIG for first-line treatment 
• Thrombopoietin receptor agonists (TPO-RAs) over rituximab or splenectomy for second-line treatment
• Rituximab over splenectomy for second-line treatment

Adult ITP

Diagnosis

ASH recommends testing adult patients with ITP for hepatitis C virus and HIV. ASH suggests further investigations if the blood count or peripheral blood smear reveals abnormalities other than thrombocytopenia and perhaps findings of iron deficiency. ASH suggests that a bone marrow examination is not necessary irrespective of age in patients presenting with typical ITP. ^[57]

Treatment

The 2019 ASH guidelines recommend against treatment of patients with a platelet count ≥30×10⁹/L who are asymptomatic or have mild mucocutaneous bleeding. For newly diagnosed adult patients with a platelet count < 30×10⁹/L, the guidelines suggest treatment with corticosterioids. For adults with a platelet count < 20×10⁹/L who are asymptomatic or have minor mucocutaneous bleeding, the guidelines suggest hospital admission for newly diagnosed patients but outpatient treatment for those with an established diagnosis of ITP. In addition, Also, those patients who are not admitted to the hospital should receive education and expedited follow-up with a hematologist within 24 to 72 hours of the diagnosis or disease relapse. ^[8]

For first-line treatment, the guidelines recommend a short course (≤6 weeks) of steroids over a prolonged course (> 6 weeks, including treatment and taper). Additional first-line treatment suggestions include the following ^[8] :

• Either prednisone (0.5-2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days) as the type of corticosteroid 
• Corticosteroids alone rather than rituximab and corticosteroids

The following 2011 ASH treatment suggestions remain unchanged ^[57] :

• IVIG may be used with corticosteroids when a more rapid increase in platelet count is required
• Either IVIG or anti-D (in appropriate patients) may be used if corticosteroids are contraindicated
• If used, IVIG should be administered in a single dose of 1 g/kg; the dose may be repeated if necessary

For adults with ITP for ≥3 months who are corticosteroid dependent or unresponsive to corticosteroids, the 2019 second-line treatment suggestions include the following, depending on preference ^[8] :

• A TPO-RA (either eltrombopag or romiplostim)
• Rituximab, for those who value avoiding surgery and long-term medication
• Splenectomy, for those who value avoiding long-term medication and gaining a durable response

The ASH guidelines recommend delaying splenectomy for at least 1 year after diagnosis, if possible, because of the potential for spontaneous remission in the first year. The 2011 recommendation that for medically suitable patients, laparoscopic and open splenectomy offer similar efficacy, also remains unchanged. ^[8]

In summary, the 2019 ASH guidelines suggest tailoring second-line therapy based on the patient's values and preferences. For those who value avoiding surgery or are not surgical candidates, a TPO-RA is preferred. Rituximab is preferred for those who value avoiding surgery and long-term medication. Finally, splenectomy should only be considered after at least 1 year has elapsed since diagnosis, given the risks of morbidity and mortality with a surgical procedure. Splenectomy should be reserved for those who value avoiding long-term medication and gaining a durable response.

While no ASH recommendations were made regarding the association of Helicobacter pylori in adult ITP, every adult with gastrointestinal symptoms with ITP or with chronic unresponsive ITP may benefit from H pylori diagnostic testing, and triple therapy should be administered to all those who test positive for H pylori infection. ^[99] Remissions after treatment of H Pylori were observed more frequently in reports from Japan and Italy (28%-100%) than in the US and other European countries (< 13%).   

ASH recommends the following tests for thrombocytopenia in pregnant patients ^[18] :

• Complete blood count
• Reticulocyte count
• Peripheral blood smear
• Liver function tests
• Viral screening (HIV, HCV, HBV)

Tests to consider if clinically indicated include the following:

• Antiphospholipid antibodies
• Antinuclear antibody (ANA)
• Thyroid function tests
• Helicobacter pylori testing
• Disseminated intravascular coagulation testing—prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, fibrin split products
• Von Willebrand disease type IIB testing*
• Direct antiglobulin (Coombs) test
• Quantitative immunoglobulin levels

The following studies are not recommended:

• Antiplatelet antibody testing
• Bone marrow biopsy
• Thrombopoeitin (TPO) levels

Treatment

Treatment considerations include the following:

•  Women with no bleeding manifestations and platelet counts ≥30×10 ⁹/L do not require any treatment until 36 weeks’ gestation (sooner if delivery is imminent).
•  If platelet counts are < 30×10 ⁹/L or clinically relevant bleeding is present, first-line therapy is oral corticosteroids or intravenous immunoglobulin (IVIG).
• The recommended starting dose of IVIG is 1 g/kg.
• Prednisone and prednisolone are preferred to dexamethasone, which crosses the placenta more readily.
• Recommended starting doses of prednisone by different experts vary from 0.25 to 0.5 to 1 mg/kg daily; no evidence exists that a higher starting dose is better.
• Medications should be adjusted to maintain a safe platelet count.

Expected responses to first-line therapy are as follows:

• Oral corticosteroids—initial response 2-14 days, peak response 4-28 days
• IVIG—initial response 1-3 days, peak response 2-7 days

Second-line therapy for refractory ITP is with combined corticosteroids and IVIG or, in the second trimester, splenectomy.  For third-line therapy, anti-D immunoglobulin and azathioprine are relatively contraindicated. Agents that are not recommended, but whose use in pregnancy has been described, include the following:

• Cyclosporine
• Dapsone
• Thrombopoietin receptor agonists
• Alemtuzumab
• Rituximab

Contraindicated agents include the following:

• Mycophenolate mofetil
• Cyclophosphamide
• Vinca alkaloids
• Danazol

Management at the time of delivery

ASH recommendations are as follows:

• Because of the possible need for cesarean delivery, the recommended target platelet count prior to labor and delivery is ≥50×10 ⁹/L.
• A woman whose platelet count is < 8010 ⁹/L but who has not required therapy during pregnancy can be started on oral prednisone (or prednisolone) 10 days prior to anticipated delivery at a dose of 10-20 mg daily and titrated as necessary.
• The mode of delivery should be determined by obstetric indications.
• Although the minimum platelet count for the placement of regional anesthesia is unknown and local practices may differ, many anesthesiologists will place a regional anesthetic if the platelet count is ≥80×10 ⁹/L.
• While platelet transfusion alone is generally not effective in ITP, its use in conjunction with IVIG can be considered if an adequate platelet count has not been achieved and delivery is emergent.
• Percutaneous umbilical blood sampling (PUBS) or fetal scalp blood sampling is not recommended, as it is not helpful in predicting neonatal thrombocytopenia and is potentially harmful.
• In the newborn, the platelet count reaches its nadir 2-5 days after delivery and rises spontaneously by day 7.
• Postpartum thromboprophylaxis should be considered, as women with ITP are at increased risk of venous thromboembolism.

Diagnosis

Basic evaluation in all patients should consist of the following ^[46] :

• Patient history
• Family history
• Physical examination
• CBC and reticulocyte count 
• Peripheral blood film
• Quantitative Ig level measurement
• Blood group (Rh)
• HIV serology - Recommended by the majority of the panel for adult patients in the appropriate geographic setting
• Hepatitis C virus serology - Recommended by the majority of the panel for adult patients in the appropriate geographic setting 
• Hepatitis B virus serology

Tests of potential utility in patients with ITP include the following:

• Glycoprotein-specific antibody (can be used in difficult cases, but has poor sensitivity and is not a primary diagnostic test)
• Antiphospholipid antibodies (including anti-cardiolipin and lupus anticoagulant) if there are clinical features of antiphospholipid syndrome
• Anti-thyroid antibodies and thyroid function
• Pregnancy test in women of childbearing potential
• Antinuclear antibodies (ANA) – A positive ANA may be a predictor of chronicity; hydroxychloroquine may be an effective treatment if ANAs are present, especially in young women; ANA testing can be considered before splenectomy because of the increased risk for thrombosis
• Polymerase chain reaction (PCR) testing for Epstein-Barr virus, cytomegalovirus, and parvovirus
• Bone marrow examination (may be informative in patients with systemic symptoms, abnormal signs, or with suspicion of a different diagnosis)
• Direct antiglobulin test Helicobacter pylori testing (should be considered in adults with typical ITP, in those with digestive symptoms, and those from areas of high prevalence)

The following tests have no proven role in the differential diagnosis of ITP from other thrombocytopenias and do not guide patient management:

• Thrombopoietin level
• Reticulated platelets/immature platelet fraction
• Bleeding time
• Serum complement

Therapy

Recommendations for initial treatment of newly diagnosed patients are as follows:

• Corticosteroids are the standard initial treatment for adults with ITP who need treatment and do not have a relative contradiction: prednisone or prednisolone at 1 mg/kg (maximum dose 80 mg, even in patients weighing >80 kg) for 2 weeks, to a maximum of 3 weeks; or dexamethasone 40 mg/d for 4 days, repeated up to 3 times
• If a response is seen (eg, platelets > 50 × 10 ⁹/L), taper the prednisone/prednisolone, aiming for discontinuation by 6 weeks (maximum 8 weeks), even if the platelet count drops during the taper.
• If there is no response to the initial dose within 2 weeks, taper the prednisone/prednisolone rapidly over 1 week and discontinue.
• Longer courses of steroids should be avoided, although occasional patients may benefit from continuous low-dose corticosteroids (eg, ≤5 mg/d).
• Use of IVIG (1 g/kg on 1 or 2 consecutive days or 0.4 g/kg per day for 5 days), or IV anti-D (50-75 µg/kg once) where available, may be appropriate in patients with bleeding, at high risk for bleeding, who require a surgical procedure, or who are unresponsive to prednisone/prednisolone. If using anti-D, exercise consideration over potential triggering of disseminated intravascular coagulation (DIC) or hemolysis, and consider steroid premedication to minimize acute infusion reactions (eg, headaches, fever-chills, and/or intravascular hemolysis).
• Patients with contraindications to high-dose corticosteroid therapy (eg, insulin-dependent diabetes, uncontrolled diabetes, psychiatric disorders, active infection) may be managed with only IVIZG or IV anti-D as initial therapy.
• TPO receptor agonists (TPO-RAs) and rituximab are not considered initial therapies.

For subsequent therapy, medications with robust evidence of efficacy are as follows:

• Rituximab
• TPO-RAs: eltrombopag, avatrombopag, romiplostim
• Fostamatinib

Medical therapies with less robust evidence are as follows:

• Azathioprine
• Cyclophosphamide
• Cyclosporine
• Danazol
• Dapsone
• Mycophenolate mofetil (MMF)
• Switching from one TPO-RA to another
• Vinca alkaloids

​Consensus-based recommendations for target platelet counts (× 10⁹/L) for dental procedures in adults are as follows:

• Dental prophylaxis (descaling, deep cleaning):  ≥20 to 30
• Simple extractions:  ≥30
• Complex extractions:  ≥50
• Regional dental block: ≥30  

Consensus-based recommendations for target platelet counts (× 10⁹/L) for surgery in adults are as follows:

• Minor surgery: ≥50 
• Major surgery: ≥80
• Major neurosurgery: ≥100

Treatment of life-threatening bleeding:

• In emergency situations in which there is an urgent need to increase the platelet count within 24 hours, a combination of initial treatments, including IV corticosteroids and, usually, IVIG, should be used. Platelet transfusions may be helpful and must not be postponed in cases of life-threatening bleeding, especially intracranial hemorrhage (ICH).
• In the case of life-threatening bleeding and the absence of a significant response to IVIG and platelet transfusion in a patient on corticosteroids, consider use of a TPO-RA.
• Additional options may include IV anti-D; vincristine or vinblastine; antifibrinolytics in combination with other initial therapies; and, rarely, emergency splenectomy.

Surgical therapy for persistent and chronic ITP:

• Splenectomy is associated with long-term treatment-free remissions. However, deferring splenectomy for ≥12 to 24 months from diagnosis before performing splenectomy is recommended because of the chance of remission or stabilization of the platelet count at a hemostatic level; up to one third of patients may remit in 1 year, and up to 80% may remit in 5 years. 
• When available, indium-labeled autologous platelet scanning may be useful prior to splenectomy to confirm that the spleen is the main site of platelet sequestration.
• Laparoscopic splenectomy is as effective as open splenectomy in terms of response and is more comfortable for the patient.
• Postoperative thromboprophylaxis should be considered in patients undergoing splenectomy as long as the platelet count is > 30 to 50 × 10 ⁹/L.
• Splenectomy should be performed by a surgeon experienced in identifying accessory splenic tissue, which is common and should be removed.
• Appropriate vaccination against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae must be provided ≥2 weeks before splenectomy and maintained according to national guidelines; recent treatment (within 6 months) with rituximab may impair vaccination efficacy.
• Patients should be informed of the long-term risks of splenectomy (ie, increased rates of thrombosis, infection, and cancer) and educated to follow advice aimed at mitigating these complications.
• Antibiotic prophylaxis should be given as per national guidelines.

Approach when multiple treatments have failed:

1. Reconsider the diagnosis
2. Perform bone marrow examination if not already done
3. Reassess the need for treatment (consider platelet count/bleeding risk)
4. Consider referral to an ITP treatment center
5. Reassess the adequacy of prior therapies (eg, was the full dose of TPO-RA explored? Did the addition of a small dose of corticosteroid improve response?)
6. Assess the risks and benefits of further treatment
7. Reassess the possibility of splenectomy if not already performed
8. Consider other medical therapies if not already attempted (eg, MMF, fostamatinib, rituximab, azathioprine, dapsone, danazol)
9. Consider enrollment in a clinical trial
10. In patients who relapse >1 year after responding to splenectomy, an accessory spleen should be searched for and, if found, resected.
11. Switching from one TPO-RA to another and sequential therapy have been shown to have a positive effect on response and adverse effects.
12. Other therapies that have been used as last resorts include combination chemotherapy, alemtuzumab, and hematopoietic stem cell transplantation (HSCT). The side effects of these treatment options may be severe, and the data supporting their use are limited.

Assessment and management of health-related quality of life outcomes

The 10-scale ITP-patient assessment questionnaire (ITP-PAQ) is an ITP-specific questionnaire that can be used to measure HRQoL, with estimated minimally important differences (MIDs) aiding interpretation. Additional measures of patient-reported outcomes (PROs) that have been studied in adult patients with ITP include the following:

• 36-item Short Form Health Survey (SF-36)
• EuroQol tool (EQ-5D)
• Hamilton anxiety and expression rating scales
• Motivation and energy inventory-short form (MEI-SF)
• Fatigue subscale of the functional assessment of chronic illness therapy (FACIT-Fatigue)
• Functional assessment of cancer therapy–thrombocytopenia (FACT-Th6)

Impaired HRQoL is multifactorial and includes (but is not limited to) issues around actual bleeding, fear of bleeding, reduced energy, depression, treatment side effects, and additive influences of underlying or comorbid diseases. Patients who respond to treatment have improved HRQoL, with those who respond to TPO-RA improving more than those who respond to other therapies; in particular, romiplostim may improve fatigue.

Other HRQoL recommendations are as follows:

• Participation in high-risk activities (eg, BMX racing, boxing, American football, ice hockey, lacrosse, motorcycle riding, motocross racing, power lifting, outdoor rock climbing, rodeo, rugby, snowmobiling, trampoline, wrestling) should be discouraged unless the patient has a near-normal platelet count on a consistent and stable basis. Alternatively, treatment should be administered to provide a safe platelet count during the activity.
• Intermittent or continuous treatment may be given to cover activities with appropriate discussion of risks vs benefits of the activity and treatment, with emphasis on psychological well-being and risks for injury, despite treatment.
• Choice of treatment and target platelet count must be carefully evaluated and based on extensive consultation and consideration of the specific activity desired and the bleeding tendency.

Diagnosis of ITP in pregnancy

Recommendations for investigation of suspected ITP in pregnancy include the following ^[46] :

• Patients with a history suggestive of ITP or those with a platelet count < 80 × 10 ⁹/L should be investigated for possible ITP (Grade C recommendation).
• As in nonpregnant patients, the diagnosis of ITP is one of exclusion using the patient’s history, physical examination, blood counts, and blood smear examination.
• Laboratory evaluation is similar to the nonpregnant patient, but special consideration should be given to rule out hypertensive, microangiopathic, coagulopathic, and hepatic disorders associated with pregnancy. Recommended tests should be based on the clinical features and may include review of the blood smear, reticulocyte count, coagulation screen, liver function, thyroid function, ANAs, and antiphospholipid antibodies.
• Bone marrow examination is not recommended unless atypical features are present.
• Anti-platelet antibody testing does not predict the course of maternal or neonatal thrombocytopenia or distinguish ITP from gestational thrombocytopenia and is not recommended.
• Testing of TPO levels is not recommended.

Treatment of ITP in pregnancy

Recommendations for the treatment of ITP during pregnancy include the following ^[46] :

• A platelet count of 20 to 30 × 10 ⁹/L in a nonbleeding patient is safe for most of pregnancy. A platelet count ≥50 × 10 ⁹/L is preferred for delivery.
• Initial treatment is with oral steroids or IVIG.
• In Rh(D)-positive nonsplenectomized women, IV anti-D appears to be well tolerated and effective; however, it may potentially cause maternal or fetal hemolysis.
• IVIG can provide a rapid, but often very transient, increase in platelet count and can be used to urgently increase platelet counts during bleeding or for delivery.
• Combining therapies (prednisone with IVIg and/or IV anti-D) may elicit a response in patients refractory to single agents alone (Grade C recommendation). High-dose methylprednisolone, in combination with IVIg and/or azathioprine, is suggested for patients refractory to oral corticosteroids or IVIg alone (Grade C recommendation).
• Rituximab can be considered in pregnancy for very severe cases, but perinatal and neonatal immunosuppression and subsequent infection are potential complications and require monitoring.
• TPO-RAs may be considered in late pregnancy when other treatments have failed, but published information is limited.
• In the rare instances when splenectomy is required, it should be performed in the second trimester.
• Vinca alkaloids, danazol, and immunosuppressive drugs not listed in these recommendations should be avoided in pregnancy.

Recommendations for obstetric analgesia and anesthesia

Recommendations for obstetric analgesia and anesthesia in women with ITP include the following ^[46] ​:

• At a platelet count ≥70 × 10 ⁹/L, in the absence of other hemostatic abnormalities, regional axial anesthesia can be safely performed.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided for postpartum or postoperative analgesia in women with platelet counts < 70 × 10 ⁹/L because of increased hemorrhagic risk.
• A platelet count ≥50 × 10 ⁹/L should be obtained for delivery.
• All women, despite having ITP, who are at an increased risk for thromboembolism should receive appropriate prophylaxis for venous thromboembolism.
• The mother with a rapidly falling platelet count should be observed more closely than those with low, but stable, levels.

Recommendations for management of delivery and newborn infants

Recommendations for delivery of women with ITP include the following  ^[46]  ​:

• Cordocentesis and fetal scalp blood sampling should be avoided in the management of the fetus/neonate of a mother with ITP in pregnancy.
• Neonatal alloimmune thrombocytopenia should be excluded by parental testing if the neonate presents with severe thrombocytopenia.
• The mode of delivery should be determined by obstetric indications, not by anticipation of the neonatal platelet count.
• Procedures during labor that may be associated with increased hemorrhagic risk to the fetus should be avoided, specifically the use of fetal scalp electrodes, fetal blood sampling, ventouse delivery, and rotational forceps.
• Previous splenectomy has been associated with worsening of maternal ITP in pregnancy and a higher risk for neonatal thrombocytopenia.
• A mother with a previous newborn, thrombocytopenic or not, is likely to have a second baby with a similar platelet count.

Recommendations for management of neonates born to women with ITP

Recommendations for the management of neonates born to women with ITP include the following ^[46] :

• Obtain umbilical cord platelet count at the time of delivery or as soon as possible.
• Repeat the platelet count as needed depending on platelet levels, trends in the count, and response to treatment (if any). If cord platelet count is < 100 × 10 ⁹/L, repeat the platelet count daily until stable. The incidence of pseudothrombocytopenia is high in neonates because of the difficulties encountered in obtaining unclotted blood with blood draws.
• If platelet count is < 50 × 10 ⁹/L at birth, perform a cranial ultrasound. A magnetic resonance imaging scan for confirmation or clarification can be performed without anesthesia using the sleep and swaddle approach 30 to 60 minutes prior.
• In the case of ICH, give IVIG and limited steroids to maintain platelet count > 100 × 10 ⁹/L for 1 week if possible and >50 × 10 ⁹/L for another week. The use of platelet transfusion may increase neonatal risk.
• If there is symptomatic bleeding or if platelet count is < 30 × 10 ⁹/L, with or without platelet transfusion, give IVIG.
• If severe thrombocytopenia continues for >1 week in a breast-fed infant, consider pausing breastfeeding for a few days to see whether platelet count increases.
• Women who had a splenectomy may have a thrombocytopenic newborn, even if their platelet count is normal.
• The only currently reliable predictor of whether a baby will be thrombocytopenic is if a previous sibling was thrombocytopenic.

 

Diagnosis

Recommendations for initial investigation of suspected childhood ITP are as follows ^[46] :

• Perform a complete history, physical examination, full blood count, and expert analysis of the peripheral blood smear at initial diagnosis.
• A direct anti-globulin test (DAT) is recommended to exclude coexistent autoimmune hemolytic anemia, especially prior to therapy.
• Baseline Ig levels, to exclude coexisting immunodeficiency, is recommended prior to therapy.
• When a child's CBC shows isolated thrombocytopenia, the peripheral blood smear shows no abnormal features beyond thrombocytopenia, and signs of bleeding are present on physical examination, a bone marrow aspiration/biopsy is not required, even prior to steroid therapy.
• Children with newly diagnosed ITP, especially with atypical features, should be referred to, or their case discussed with, a hematologist experienced in assessment and treatment of children with ITP.
• Bone marrow aspiration, biopsy, and cytogenetics should be performed if abnormal or potentially malignant cells are visualized on smear and carefully considered if there are other abnormalities of the hemoglobin and/or white cell count (with the exception of microcytic anemia) or if there is hepatosplenomegaly and/or adenopathy. In addition, failure to acutely respond to ITP therapy merits a bone marrow examination.
• Additional investigations are based on clinical assessment and may include tests insuch as molecular genetics, autoantibody screening, liver-spleen imaging, and other laboratory testing

Recommendations for subsequent investigation of children with persistent or chronic ITP are as follows:

• Perform a repeat history, physical examination, full blood count, and expert analysis of the peripheral blood smear to reassess the diagnosis.
• Perform bone marrow aspiration, biopsy, and cytogenetics if no spontaneous platelet increase and no response to treatment has occurred after 3 to 6 months, or earlier if there is no response to treatment within the expected timeframe. Consider next-generation sequencing or targeted sequencing, if available.
• A bone marrow biopsy is not indicated prior to further therapy (eg, with TPO), but should be included in reevaluation of the diagnosis in the setting of increasingly difficult-to-treat persistent or chronic ITP.

Additional evaluation could include testing for the following:

• Lupus and other markers of autoimmune diseases that might require specific treatment (eg, test for APLAs, ANAs, anti-cardiolipin antibody, lupus anticoagulant, and serum Igs)
• Chronic infections (hepatitis, cytomegalovirus, HIV, and/or H pylori in at-risk populations or when there is no other explanation)
• Complex immunodeficiency diseases
• Genetic screening for inherited thrombocytopenia and bone marrow failure syndromes

Management

A bleeding scale for pediatric patients with ITP is shown in Table 1, below.

Table 1. Bleeding scale for pediatric patients with ITP (Open Table in a new window)

Watch-and-wait

Recommendations for a watch-and-wait policy, based on clinical classification, are as follows:

• At diagnosis, children and adolescents with ITP and mild or even moderate bleeding on a pediatric bleeding assessment tool (grade 1-3) may be managed expectantly with supportive advice and a 24-hour contact point, irrespective of platelet count
• Those with grade 3 bleeding are more likely to require therapy because of the higher rates of serious bleeding requiring hospital admission and emergency treatment.
• All patients need regular reevaluation to monitor for worsening, including health-related quality of life (HRQoL) and evolution to a serious bone marrow disorder or a secondary form of ITP. The frequency of clinical and laboratory monitoring should be based on bleeding, HRQoL, trend in platelet counts, and impression of family reliability.
• The same monitoring and 24-hour access are needed with persistent and chronic ITP, depending upon the factors listed above, but at less frequent intervals in a stable patient. Observation or watch-and-wait is less validated in patients with persistent and chronic ITP because it is based on the expectation of spontaneous future improvement.

Indications for treatment

Recommendations for when to start initial treatment in children newly diagnosed with ITP are as follows:

• Any severe (grade 4) bleeding requires immediate hospital admission and treatment to increase platelet levels until bleeding has decreased.
• Any moderate (grade 3) bleeding requires hospital review and consideration for admission and therapy.

Administer treatment and strongly consider hospitalization in the following cases:

• Worsening bleeding or significant comorbidities
• Risk of ICH (eg, head trauma or unexplained headaches); patients at higher risk for ICH include those with a history of moderate or severe bleed in the preceding 28 days, recent administration (within 8 hours) of NSAIDs, and another clinically significant coagulopathy (eg, von Willebrand disease). In the case of head trauma, treatment should precede a head computed tomography scan.
• A change in behavior or mood consistent with significant depression or irritability
• Parents are anxious about bleeding and do not believe that they can control (young child) or restrict (older child) their child’s activity.
• Parents cannot be relied upon to bring the child back readily if there is an emergency (eg, they live too far away, they cannot afford to return, there are additional social concerns).
• Child has not spontaneously improved and must be overly restricted in activities.
• Child needs to take an anticoagulant or antiplatelet agent.
• Higher risk of bleeding due to another medical or psychological issue

Initial treatment regimens:

• If the patient has moderate or severe bleeding, IVIG and anti-D can often increase the platelet count to hemostatic levels (>50 × 10 ⁹/L) within 24 to 48 hours. IVIGg is effective when given as a single dose of 0.8 to 1.0 g/kg. Anti-D has similar efficacy to IVIG when given as a single dose of 75 µg/kg and is rarely associated with severe hemolysis. High-dose steroid premedication is recommended for IV anti-D and is useful for IVIG.
• A second dose of IVIg or anti-D may be administered if there is a suboptimal initial response and/or ongoing bleeding.
• Give prednisone/prednisolone at 4 mg/kg per day in 3 or 4 divided doses for 4 days with no taper, with a maximum daily dose of 200 mg or at 1 to 2 mg/kg, with an 80-mg maximum daily dose, even in patients weighing >80 kg, for 1 to 2 weeks. If a response is seen (eg, platelets > 50 × 10 ⁹/L), taper the prednisone/prednisolone, aiming to stop it by 3 weeks, even if the platelet count drops during the taper.
• If there is no response to the initial dose within 2 weeks, taper the prednisone/prednisolone rapidly over 1 week and stop it.
• In general, corticosteroids are used for grade 1 or 2 bleeding or for patients not responsive to IVIG.
• IV anti-D can be used if the patient is Rh positive, not splenectomized, does not have a positive direct Coombs test (DAT), and has hemoglobin ≥9 g/dL.

Emergency treatment:

• Combination therapy, including platelet transfusions, IV corticosteroids, and IVIG, with or without anti-D, is recommended. Administer platelet transfusions as a bolus, followed by continuous infusion in combination with IV high-dose steroids (eg, IV methylprednisone/prednisolone, 30 mg/kg per day). For ICH or other life-threatening or serious bleeding, give IVIG (0.8-1.0 g/kg per day, with or without single-dose IV anti-D (75 µg/kg). A second dose of IVIG and IV steroids may be required if a platelet response is not seen within 24 hours of the initial dose.
• IVIG, steroids, and IV anti-D (if available) can be used to attempt to ensure the most likely and fastest platelet increase. Antifibrinolytics may be given if bleeding continues despite therapy.
• In patients with an ICH, emergency splenectomy and/or neurosurgical control of bleeding should be considered in conjunction with emergency platelet-raising therapy, but medical treatment should never be delayed because of surgical or radiologic intervention if at all possible.
• TPO-RAs should be considered, as they may aid the acute response in patients and prevent a decrease in platelet count if initial response to emergency therapy is lost.

Treatment of persistent or chronic ITP:

• Most children with persistent or chronic ITP can be managed with watchful waiting. If an acute bleeding episode occurs, rescue therapy with corticosteroids, IVIG, and/or IV anti-D can be used.
• Children who are having frequent or severe bleeding episodes or impaired HRQoL (including reduction in important activities) require referral to a hematologist experienced in treating pediatric ITP.
• TPO-RAs often produce a good response and reduction in bleeding frequency, with an absence of adverse effects in the majority of patients. If the patient does not respond to a TPO-RA or loses response, switch to an alternative TPO-RA and/or consider combining with MMF or another immunosuppressant.
• Consider rituximab and dexamethasone for patients, especially adolescent girls, in whom TPO-RAs fail.

Splenectomy:

• Splenectomy is very rarely indicated in childhood ITP, and should be undertaken in consultation with a hematologist experienced in the management of children with ITP. It should only be considered in children who have failed all available medical therapies, are having thrombocytopenia-related bleeding, and whose life is at risk or whose HRQoL is substantially impaired.
• Splenectomy should be avoided if at all possible before 5 years of age and within 1 year of disease onset.
• Before considering splenectomy, reassess the diagnosis of ITP by excluding alternative diagnoses, including inherited thrombocytopenia, bone marrow failure, drug-induced thrombocytopenia, subclinical viral infections, immunodeficiency syndromes (eg, common variable immune deficiency [CVID], autoimmune lymphoproliferative syndrome), and myelodysplastic syndrome.
• Prior to splenectomy, ensure that vaccinations are up to date according to national policy. Vaccination, as a minimum, should include pneumococcal 13-valent conjugate vaccine, followed by pneumococcal 23-valent vaccine 4 weeks later; H influenzae type B; and both meningococcal vaccines to cover all 5 species subtypes.
• If there is any concern for an immunodeficiency-related ITP, even if undocumented, reducing the risk for postsplenectomy sepsis by assessing response to pneumococcal vaccines preprocedure is advisable.

Health-related quality of life considerations:

• HRQoL should be reported using the Kid’s ITP Tool (KIT) or another validated scale before and after treatment, to assess the effect of treatment beyond the platelet count.
• Corticosteroids may worsen HRQoL in children with ITP; TPO-RAs may improve their HRQoL, and romiplostim especially appears to improve parental burden.

School and participation in sporting activities:

• Children and adolescents 5 to 18 years old need ≥60 minutes of physical activity per day, ≥3 d/wk. This should include exercises or sports to promote strong muscles and bones.
• Normal attendance and play at kindergarten, school, or college, depending on age, is essential. The risk of bleeding and information about ITP should be provided to the school in a way that facilitates inclusion, not isolation.
• Active participation in low-risk activities should be maintained, irrespective of platelet count and treatment.
• Participation in non–low-risk activities must be discussed with the family, school, and coach. A number of factors must be considered prior to participation, including age of the child, platelet count, bleeding history, and physical nature of the activity.