Immune thrombocytopenia (ITP) is an acquired autoimmune disease associated with an increased risk of bleeding in adults and children.1 It is characterized by platelet counts of less than 100 × 109/L and reduced platelet production. ITP can occur in isolation (primary ITP) or in approximately 20% of patients, can occur in association with other diseases including systemic lupus erythematosus and immune deficiencies such as selective immunoglobulin A deficiency, and autoimmune lymphoproliferative syndrome (secondary ITP).2
Patients with ITP may experience increased bleeding risk, fear of engaging in activities that may increase bleeding episodes, fatigue, depression, reduced emotional health, lack of desire to socialize, and changes on sexual well-being resulting in negative impacts on their health-related quality of life (HRQOL).3
According to the duration of disease, ITP is classified as “newly diagnosed, persistent” if the disease duration is between 3 to 12 months or “chronic” if the disease duration is at least 12 months. The disease course is usually chronic in adults whereas about 90% of children experience spontaneous remission within weeks to months after disease onset.4
Among adults of reproductive age, ITP is more common in women than men and is more common in women who are pregnant than women who are not (Figure).5,6 The estimated annual incidence of ITP in the United States from 2012 to 2015 was 6.1 per 100,000 people; nearly 20,000 children and adults were newly diagnosed each year.6 The collective medical care costs are more than $400 million in the first 12 months after diagnosis.6
Treatment of ITP starts with a correct diagnosis. However, varying disease presentation and the lack of a gold standard diagnostic test makes a differential diagnosis challenging. Anti-platelet antibody testing is not helpful because the presence of antibodies is not specific to ITP and the absence of antibodies does not exclude ITP. Therefore, ITP is often diagnosed by exclusion while recognizing other often-overlooked causes, such as myelodysplastic syndrome, drug-induced thrombocytopenia, and cyclical thrombocytopenia.7,8
For patients newly diagnosed with ITP, the American Society of Hematology (ASH) guidelines recommends initiating treatment when their platelet count falls below 30 × 109/L regardless of the presence of bleeding.9 The goal of treatment is to increase platelet counts to within a hemostatic range to decrease bleeding risk.4
Therapeutic Management of ITP
The first-line treatments for the management of ITP include corticosteroids (prednisone or dexamethasone), intravenous immunoglobulin, and anti-D immunoglobulin.9,10 The primary treatment goals are to halt active bleeding events, limit future hemorrhage, and achieve a sustained increase in platelet count with minimal adverse effects.
Although first-line treatments provide a rapid platelet response, the response is typically lasts less than 6 months. Patients must be repeatedly treated until their platelet count stabilizes.11 The adverse effects associated with first-line therapies, including osteoporosis, diabetes, growth retardation, and weight gain, preclude their long-term use. Some patients experience relapse of ITP despite an initial response to therapy.12-14
To prevent the misuse of corticosteroids and improve long-term clinical outcomes, patients should switch from treatment with corticosteroids to alternative options earlier in the course of treatment.15 Consequently, second-line treatments are needed to achieve more durable responses. Although treatment options are now available in the second-line setting, disease management remains a challenge owing to a lack of consensus on optimal treatment selection and initiation.15
Second-line Treatment Options
The current treatment options used in the second-line setting include thrombopoietin receptor agonists (TPO-RAs), splenectomy, rituximab (Table).9 The choice of therapy is determined by likelihood of remission, patient preference, adverse effects, route of administration, and cost.
Currently, no head-to-head comparisons of the efficacy of these treatment options are available.16 A retrospective analysis compared eltrombopag, romiplostim, rituximab, and splenectomy as second-line treatments for ITP, with a specific focus on the impact of treatment on platelet counts, bleeding-related episodes, thrombotic events, and use of rescue medication. The results showed that while all 4 treatments were associated with significant increases in platelet count, patients treated with TPO-RAs experienced a longer treatment-free period.17
The goal of splenectomy is to stop platelet destruction. Traditionally, splenectomy is the second-line treatment of choice for adults and children who do not respond to first-line agents or who do not achieve long-term remission. Splenectomy offers a higher durable response rate of 77% compared with other ITP therapies.18,19 The ASH guidelines recommended that splenectomy be avoided in the first 12 months after ITP diagnosis to allow for spontaneous or therapy-induced remissions, particularly in young children who generally have high rates of spontaneous remission and in older patients who have increased surgical morbidity and lower rates of response.9,10
Although splenectomy can be associated with increased risk for infections, cardiovascular complications, bleeding, and thrombosis, it remains a reasonable treatment for patients who prefer medication-free management of their disease.20 Patients who are candidates for splenectomy should first receive appropriate immunization. Patients should also taught how to recognize and manage treatment-related fever consistent with current pre- and postsplenectomy care recommendations.9
The rate of splenectomy in the United States and Europe has declined recently because of the availability of, and patient preference for, alternative treatment options such as rituximab and TPO-RAs. 21-23
This anti-CD20 monoclonal antibody promotes rapid depletion of the CD20-positive B cells responsible for antibody production, decreased serum immunoglobulin levels, and an increased number of T-regulatory cells. Rituximab is a therapeutic candidate for second-line treatment of ITP in patients with suboptimal responses to first-line therapy.26,27 In patients treated with rituximab after an initial response to first-line therapy followed by relapse, high response rates of up to 92% have been reported with a durable response and good safety profile.9,27
Adverse events including rash, urticaria, fever, myalgia, headache, and transient hypertension are associated with infusion reactions. A risk for hypogammaglobulinemia has been reported in patients who receive multiple courses of rituximab.28,29 Other rare but potentially fatal complications include reactivation of underlying hepatitis and tuberculosis, multifocal leukoencephalopathy, and severe mucocutaneous reactions.30,31
Although the response to rituximab appears to wane over time, rituximab remains an effective treatment option for some patients.32,33 Although combination treatment with rituximab and corticosteroids has been proposed as first-line therapy, the quality of evidence for concomitant use is low, according to the ASH guidelines; until more robust data are available, corticosteroids alone are favored.9
Thrombopoietin Receptor Agonists
TPO-RAs are currently the only therapy specifically developed to treat ITP. These agents stimulate platelet production by binding to the transmembrane domain of the thrombopoietin receptor and inducing proliferation and differentiation of megakaryocytes. TPO-RAs have been shown to be effective and safe in randomized clinical trials, reduce bleeding events and the need for emergency treatments, and improve HRQOL in patients with chronic ITP.34-36
The TPO-RAs approved by the US Food and Drug Administration (FDA) for second-line treatment of ITP are avatrombopag, eltrombopag, and romiplostim (Table).37-39 As many as 30% of patients treated with TPO-RAs may achieve long-term remission.14
Avatrombopag. Avatrombopag is administered orally and have benefits in specific patient populations. Avatrombopag is superior to placebo in reducing platelet transfusions or rescue procedures for bleeding in patients with chronic liver disease. Avatrombopag can be considered to treat thrombocytopenia in patients with chronic liver disease scheduled to undergo an invasive procedure.40
Eltrombopag. In some patients, long-term use of eltrombopag is associated with improvement in HRQOL, such as reduced fatigue, reduced concern about bleeding, and improved physical function.2,41 A treatment-free period is possible with eltrombopag in a substantial minority of patients.2 Eltrombopag is administered orally and showed similar effectiveness compared with avatrombopag in improving platelet counts in patients with primary and secondary ITP.
Romiplostim. Romiplostim is administered as a once-weekly subcutaneous injection and is associated with improved HRQOL. Given the high platelet response rate, romiplostim may be most beneficial in patients with persistent bleeding.24
Failure of one TPO-RA does not preclude the use of another and switching from one TPO-RA to another may be appropriate for some patients.42
TPO-RAs are generally well tolerated. Nonbleeding-related adverse events commonly include nausea, fatigue, headache, diarrhea, pyrexia, abdominal pain, and insomnia. Significant adverse effects are bone marrow fibrosis and thrombotic events. In general, adverse events can be reversed with the discontinuation of treatment.43 Given the safety and efficacy data, TPO-RAs are the preferred second-line treatment for patients with ITP.9
Fostamatinib is a spleen tyrosine kinase inhibitor approved for the treatment of chronic ITP.44 Fostamatinib was primarily studied in the third-line setting and its role as a second-line agent has not been established.
Overall Guideline Recommendations
The ASH guideline panel conditionally recommends the following treatment options in adults with ITP lasting ≥3 months who are corticosteroid dependent or have no response to corticosteroids9:
- Either splenectomy or a TPO-RA
- TPO-RAs are recommended over rituximab
- Rituximab is recommended over a splenectomy
Second-Line Treatment Selection and Management in Specific Populations
The choice of treatment should be based on disease duration, frequency of bleeding episodes, the patient’s age, comorbidities, treatment preference regarding adverse effects, route of administration, cost, and effects on HRQOL.18 The ASH guidelines provide an algorithm for selection of a second-line therapy that emphasizes shared decision-making between physicians, patients, and families.9
Management in Children
- Most children with persistent or chronic ITP can be managed with watchful waiting. If an acute bleeding episode occurs, rescue therapy with corticosteroids, intravenous immunoglobulin, and/or intravenous anti-D immunoglobulins is indicated.
- Children with frequent or severe bleeding episodes (sufficient to affect daily activities) require referral to a hematologist experienced in treating pediatric ITP.
- TPO-RAs often elicit a good response with minimal adverse events. If the patient does not respond or loses response to a TPO-RA, switch to an alternative TPO-RA and/or consider combining with mycophenolate mofetil or another immunosuppressant.
- Consider rituximab and dexamethasone for patients, especially adolescent girls, who do not respond to TPO-RAs.
Management in Adults
- Consider second-line therapy in adults with ITP lasting 3 months or longer who are corticosteroid dependent or have no response to corticosteroids and adults who have had ITP for 12 months.
- TPO-RAs are the preferred second-line therapy over splenectomy and rituximab. Some exceptions to receiving TPO-RAs include:
- Patients who prefer to avoid long-term medication may prefer splenectomy or rituximab;
- Patients who wish to avoid surgery may prefer a TPO-RA or rituximab; and
- Patients who place a high value on achieving a durable response may prefer splenectomy or TPO-RAs.
- The ASH guidelines recommend that splenectomy be performed after failure of pharmacologic therapies in the chronic phase of ITP and at least 12 months from diagnosis.
Management in Pregnant Women10
- For most pregnancies, a platelet count of 20 to 30 × 109/L in a nonbleeding patient is safe; a platelet count of 50 × 109/L or higher is preferred for delivery.
- Rituximab can be considered in pregnancy in very severe cases. Monitoring for perinatal and neonatal immunosuppression and subsequent infection is recommended.
- TPO-RAs may be considered in late pregnancy when other treatments have failed but published data are limited.
- In the rare instances when splenectomy is required, it should be performed in the second trimester.
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- Patwardhan P, Landsteiner A, Lal LS, et al. Eltrombopag treatment of patients with secondary immune thrombocytopenia: retrospective EHR analysis. Ann Hematol. 2022;101(1):11-19. doi:10.1007/s00277-021-04637-2
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- Guillet S, Loustau V, Zarour A, et al. Outcome of immune thrombocytopenia in pregnancy: a French nationwide prospective multicenter observational case-control study. Blood. 2020;136(Supplement 1):13-14. doi:10.1182/blood-2020-140329
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Reviewed June 2022