Version July 2025
INTRODUCTION —
Therapy for immune thrombocytopenia (ITP) requires clinical judgment and incorporation of patient values and preferences. Many individuals do not require any treatment; others have a remission or response with only first-line therapy with glucocorticoids; and others continue to have severe thrombocytopenia necessitating additional therapy.
This topic discusses an approach to management of ITP for adults who require second-line therapy, defined as additional therapy beyond first-line therapy with glucocorticoids (with or without intravenous immune globulin [IVIG]). Separate topics discuss the clinical manifestations, diagnosis, and initial treatment of adults and children with ITP.
●Adults
•Diagnosis – (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)
•Initial treatment – (See "Initial treatment of immune thrombocytopenia (ITP) in adults".)
●Children
•Diagnosis – (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)
•Initial treatment – (See "Immune thrombocytopenia (ITP) in children: Management of newly diagnosed patients".)
•Chronic disease – (See "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease".)
●Pregnancy – (See "Thrombocytopenia in pregnancy", section on 'Immune thrombocytopenia (ITP)'.)
INITIAL CONSIDERATIONS
Treatment of bleeding — Treatments for acute, severe bleeding or urgently needed platelet count increase for surgery or obstetric indications are discussed separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Critical or severe bleeding' and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Surgery or delivery'.)
Indications for second-line therapy and caveats before starting a second-line treatment
●Goal – The goal of ITP therapy is to provide a safe platelet count to prevent clinically important bleeding, not necessarily to normalize the platelet count [1].
●Indications – Second-line therapy is used when first-line therapy with a glucocorticoid does not raise the platelet count to a safe level, or if tapering the glucocorticoid results in a decrease of the platelet count below a safe level (algorithm 1). (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Whom to treat (indications for therapy)'.)
●Diagnostic confirmation – Before determining that a glucocorticoid is ineffective, it is worth reviewing the initial diagnosis to ensure there is not another cause of persistent thrombocytopenia. If a hematologist was not previously involved in diagnosis and treatment, their input at this stage is essential. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Additional testing in selected patients'.)
Non-ITP diagnoses with isolated thrombocytopenia include inherited platelet disorders, liver disease, consumptive thrombocytopenias, drug-induced thrombocytopenia, and myelodysplastic syndrome (MDS). These and others are discussed separately. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Differential diagnosis' and "Diagnostic approach to thrombocytopenia in adults", section on 'Categories of causes'.)
ITP is characterized by platelet count variability over time [2]. Platelet counts that remain constant without significant fluctuations suggest that ITP may not be the correct diagnosis.
In one series of 295 individuals who were initially diagnosed as having ITP, 36 (12 percent) were subsequently reclassified as having a different diagnosis requiring a different management approach [3].
●Secondary ITP – Review possible causes of secondary ITP that might respond to treatment of the underlying condition, such as Helicobacter pylori infection, HIV infection, hepatitis C virus (HCV) infection, inflammatory diseases, large granular lymphocyte disorders, or chronic lymphocytic leukemia (CLL) [1]. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Inciting events'.)
●Platelet count threshold – We often initiate second-line therapy at a slightly lower platelet count than used for initial therapy (platelet count <20,000/microL rather than <30,000/microL that is used for initial therapy), especially if the platelet count <20,000/microL is recurrent or associated with bleeding symptoms (mucosal purpura or more serious bleeding). Otherwise, lower platelet count levels may be well tolerated.
●Duration of ITP – A 2019 guideline on ITP from the American Society of Hematology (ASH) considers second-line therapy to be appropriate for these individuals after ≥3 months from diagnosis [1]. However, it is reasonable to start second-line therapy before three months in patients who do not have a response to first-line therapy or who experience a relapse after a glucocorticoid is tapered. The ASH guideline and an associated consensus report emphasize that therapy should minimize toxicity and optimize the patient's quality of life [1,4].
●Bleeding risk factors – The platelet count threshold for second-line therapy is generally greater for patients with any of the following:
•Higher risk of bleeding due to other comorbidities (eg, hypertension or chronic kidney or liver disease)
•Need for concomitant antiplatelet agents or anticoagulant medications
•Athletic activities, careers, or lifestyles with high risk for trauma.
For patients for whom bleeding is less of a concern, second-line therapy may be deferred even at lower platelet counts.
Vaccinations — All age-appropriate vaccinations should ideally be administered before any immunosuppressive therapy such as rituximab or splenectomy. This includes vaccinations against encapsulated organisms. While it is optimal to allow sufficient time for a vaccine response, initiation of therapy for ITP should not be delayed while awaiting a serologic response if therapy is deemed to be required more urgently.
Vaccination details are presented separately. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Vaccinations' and "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations' and "Overview of infections associated with immunomodulatory (biologic) agents".)
Individuals with chronic ITP do not need to delay vaccination, and COVID-19 vaccination should not be withheld for individuals who have received (or are receiving) ITP therapy and are not in the midst of a flare. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'COVID-19 vaccination'.)
Patients and clinicians should be informed about the possible reduced vaccine response after rituximab and the importance of taking other precautions against viral illnesses such as COVID-19 during and after treatment with immunosuppressive therapies. Patients and clinicians are advised to review the latest recommendations with respect to booster vaccine doses in patients who are receiving immunosuppressive therapy. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)
CHOICE OF SECOND-LINE THERAPY
How to choose a second-line therapy — The four principal choices for second-line therapy are [5,6]:
●Splenectomy
●Rituximab
●A thrombopoietin receptor agonist (TPO-RA) such as eltrombopag, avatrombopag, or romiplostim
●Fostamatinib
All are effective in raising the platelet count, but they differ dramatically in their mechanisms of action, administration, duration, costs, burdens, and adverse effect profiles. Relative efficacies and toxicities are discussed below. (See 'Relative efficacy and toxicity profiles' below.)
As a result, the choice of therapy is highly dependent upon patient characteristics and values and preferences. We discuss all of these options with patients and assist them in balancing the risks and benefits of each approach, which are summarized in the table (table 1) and illustrated in the decision tree (algorithm 2).
●Splenectomy – Splenectomy is a surgical procedure that is the most likely of the second-line therapies to result in a durable response without ongoing need for medication.
Splenectomy may be a good choice for an individual who wishes to have a single potentially curative surgical procedure and who is willing to accept the increased risks of infection (due to lifelong immunosuppression) and venous thromboembolism (VTE). Compared with open splenectomy, laparoscopic splenectomy has a lower mortality and complication rate, shorter hospitalization, and faster recovery. Splenectomy in patients with ITP is often performed at platelet counts that might otherwise be considered too low for a major surgical intervention.
If splenectomy is chosen, it is generally preferable to wait at least one year from the time of ITP diagnosis in case a remission occurs. During this time, another medication can be used to increase the platelet count [7]. Pre-splenectomy vaccinations are critical. (See 'Decision to pursue splenectomy' below and 'Vaccinations' above.)
●Rituximab – Rituximab is a monoclonal antibody directed against CD20 on B lymphocytes.
Rituximab may be a good choice for an individual who wishes to avoid surgery and prefers not to take a medication long term. However, it requires four weekly intravenous infusions, and its effect can be short-lived, necessitating repeat dosing or use of another second-line agent. (See 'Rituximab evidence for efficacy' below.)
Rituximab causes prolonged (but not indefinite) immune suppression and increased risk for certain infections, including COVID-19. (See 'Rituximab' below.)
●TPO-RAs – These drugs stimulate the TPO receptor, causing increased platelet production.
A TPO-RA may be a good choice for an individual who wishes to avoid immunosuppression and who is less concerned about the need to take a medication for an extended period of time, including the associated costs and burdens. (See 'Decision to use a TPO-RA' below.)
TPO-RAs generally require regular administration as a maintenance therapy, although responses are sometimes sustained after the treatment is stopped. Romiplostim is a once-weekly subcutaneous injection; eltrombopag and avatrombopag are once daily pills.
TPO-RAs may cause bone marrow fibrosis (reversible) and hepatotoxicity, and they may increase the risk of thrombosis and thromboembolism.
●Fostamatinib – Fostamatinib inhibits a tyrosine kinase that affects Fc-receptor signaling and autoantibody production.
Fostamatinib may be a good choice for an individual who is especially concerned about avoiding immunosuppression and/or surgical risks and who does not have access to a TPO-RA. It is administered as a twice daily pill.
Adverse effects of fostamatinib include diarrhea, rash, hypertension, and neutropenia.
The 2019 American Society of Hematology (ASH) guideline on ITP made weak recommendations for a TPO-RA over rituximab, for rituximab over splenectomy, and for splenectomy or a TPO-RA, but the guideline emphasized the potential usefulness of all three treatments and the importance of patient characteristics (age, ITP history, comorbidities), values, and preferences in the final decision [1]. This guideline predated the incorporation of fostamatinib as a potential second-line therapy.
Some experts prefer other therapies, such as mycophenolate mofetil (MMF), despite having less evidence from randomized trials. (See 'Other therapies' below.)
Relative efficacy and toxicity profiles
●Efficacy – Overall efficacies of splenectomy, rituximab, TPO-RAs, and fostamatinib are discussed in the sections below. (See 'Decision to pursue splenectomy' below and 'Rituximab evidence for efficacy' below and 'TPO-RAs efficacy and adverse events' below and 'Fostamatinib efficacy and adverse events' below.)
Comparisons of these therapies (or any pairwise combinations) in randomized trials are not available [8]. However, the reported initial response rates with splenectomy are higher than with rituximab (60 to 80 percent versus 55 to 65 percent, respectively) and responses with splenectomy are more durable (often lasting for many years or even indefinitely for splenectomy, versus one to two years for rituximab) [9-15]. Responses are much more predictable with TPO-RAs and fostamatinib, but they require ongoing therapy.
●Toxicity – Short-term and long-term risks and burdens differ significantly among these therapies that may factor into decision-making depending on the patient's underlying risk factors and values and preferences. Examples of the differing risks include:
•Immunosuppression – Splenectomy and rituximab are immunosuppressive (splenectomy indefinitely; rituximab for a prolonged period of time). There are also significant differences in short-term and long-term risks of splenectomy versus rituximab (table 1) [16,17].
•Thrombosis – Splenectomy and TPO-RAs both increase the risk of thrombosis, with a greater increase in risk with splenectomy.
•Other adverse effects – Fostamatinib can cause hypertension, diarrhea and neutropenia. TPO-RAs can cause bone marrow fibrosis (reversible) and hepatotoxicity (eltrombopag only). Platelet count monitoring is important to avoid thrombocytosis.
SPLENECTOMY —
Splenectomy removes the major site of phagocytosis of antibody-coated platelets, as well as lymphocytes that reside in the spleen that might be responsible for producing antiplatelet antibodies. It therefore effectively targets multiple pathophysiologic mechanisms of ITP and has the greatest potential to modify the course of the disease [18]. (See "Splenomegaly and other splenic disorders in adults", section on 'Properties of the normal spleen'.)
Decision to pursue splenectomy — Splenectomy may be a good choice for an individual who wishes to have a single potentially curative surgical procedure and who is willing to accept the small increased risks of infection and venous thromboembolism (VTE). Preference for splenectomy may also correlate with local surgical expertise. (See 'Choice of second-line therapy' above.)
If splenectomy is pursued, it is generally prudent to wait at least 12 months from diagnosis since remissions are possible. (See 'Timing of splenectomy' below.)
●Efficacy – Of all the ITP therapies, splenectomy has the greatest chance of altering the disease course and resulting in a sustained remission [9,19].
The high rate of sustained remission with splenectomy was illustrated in a systematic review of splenectomy for ITP that included data for 47 case series (2623 adults) and over 50 years of observation, published in 2004 [9]. Platelet counts normalized in 66 percent of individuals and increased to >50,000/microL in an additional 22 percent, for a total response rate of 88 percent. Responses persisted throughout the duration of monitoring (up to over 12 years) (figure 1).
A subsequent study from 2022 that included 185 individuals with ITP who underwent splenectomy confirmed that splenectomy is still an appropriate option [20]. Most participants had received prior rituximab (73 percent) or a TPO-RA (54 percent). Initial response to splenectomy occurred in 78 percent, with sustained response in 65 percent, like the pre-TPO-RA era.
●Predicting response – The only clinical parameter that predicts a favorable response to splenectomy is patient age; younger patients have a higher response rate, although a specific age cutoff below which splenectomy was most effective could not be determined [9,21-24]. One study reported that the duration of response following splenectomy and the likelihood of response may be reduced in patients older than 65 years [22]. Another study found a correlation between response to intravenous immune globulin (IVIG) and response to splenectomy [25]; however, this may represent better patient selection.
Platelet counts typically rise within the first two weeks postoperatively (table 2). Platelet count increases within one to two days can also occur, and delayed responses (up to eight weeks or longer) have been observed [26].
In some centers, a radiolabeled tracer scan (indium, chromium) is used to determine the degree of splenic sequestration of platelets, which is thought to correlate with the likelihood of a good response to splenectomy. A 2020 meta-analysis of studies using this approach in 2966 individuals with ITP demonstrated a correlation between a splenic sequestration pattern and a good response to splenectomy relative to other patterns (hepatic, mixed, or unknown) [27]. Response rates were 87 percent with a splenic pattern versus 47 percent with a mixed pattern and 26 percent with a hepatic pattern. This type of scanning to predict response to splenectomy is not routinely used in North America.
●Adverse effects – Splenectomy has the greatest associated risks of second-line therapies, including operative risks and postoperative risks of immunosuppression and increased rate of thromboembolic complications [28]. In a systematic review that included 47 case series of splenectomy for ITP, complications occurred in 88 of 921 patients who underwent laparoscopic splenectomy (10 percent) and 318 of 2465 who underwent open splenectomy (13 percent) [9]. These and other potential complications are discussed in detail separately. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Postoperative risks'.)
The table compares the risks of splenectomy with the risks of other second-line therapies (table 1).
●Accessory spleen – For patients with persistent thrombocytopenia following splenectomy, we generally proceed to another approach, such as rituximab, a TPO-RA, or one of the approaches listed below. (See 'Other therapies' below.)
We generally do not pursue a diagnosis of an accessory spleen or perform accessory splenectomy in patients with persistent thrombocytopenia following splenectomy. However, this approach has been used in rare patients who have a late recurrence of ITP after splenectomy. Absence of Howell-Jolly bodies (picture 1) on the peripheral blood smear may be a clue to persistent splenic tissue or splenic tissue regrowth. (See "Evaluation of the peripheral blood smear", section on 'Howell-Jolly, Heinz, and Pappenheimer bodies'.)
Timing of splenectomy — Decisions about when to perform splenectomy can be challenging because of the possibility of a late remission. Many clinicians prefer to delay splenectomy with the hope that a remission will occur and render the procedure unnecessary [18]. However, data to predict which patients will have remission (and thus might avoid splenectomy) are lacking, and there is not a clear cutoff time after which such remissions become less likely.
We individualize the timing of splenectomy based on the patient's clinical features, response to initial therapy, and other considerations (eg, patient preference). In practice, we often wait at least 12 months from diagnosis of ITP to splenectomy to allow for remissions; this practice is consistent with the 2019 ASH ITP guidelines [1]. Some patients with persistently severe and symptomatic thrombocytopenia despite medical therapy may require splenectomy sooner.
Pre-splenectomy considerations — Additional issues for patients considering splenectomy include the following:
●Immunizations – Patients considering splenectomy should receive immunizations for encapsulated organisms at least two weeks before the procedure if possible and if these were not done already. These individuals are often prescribed antibiotics to take in the event of fever. Details of the impact of immunosuppression on response to vaccination, specific vaccination schedules, and other infection prevention are discussed separately. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Preoperative considerations' and "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations' and "Prevention of infection in patients with impaired splenic function", section on 'Emergency antibiotic supply'.)
●Optimizing the preoperative platelet count – If the platelet count needs to be increased for splenectomy, the patient can be treated with intravenous immune globulin (IVIG), glucocorticoids, or a thrombopoietin receptor agonist (TPO-RA). We prefer to perform splenectomy with a platelet count of ≥50,000/microL; however, many patients with ITP have undergone open or laparoscopic splenectomy safely in the setting of more severe thrombocytopenia, with platelets available for transfusion if urgently needed because of intraoperative bleeding [29]. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Surgery or delivery'.)
●Operative technique – Laparoscopic splenectomy has become the standard operative technique [18]. This is based on the lower rates of morbidity and mortality reported in a systematic review that included over 3000 splenectomies in patients with ITP (mortality rate of 1 percent with open and 0.2 percent with laparoscopic procedures) [9]. Practices and surgical outcomes may differ at different institutions. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Surgical approach'.)
Other general preoperative considerations (eg, cardiac risk assessment and preoperative thyroid function testing) are presented separately. (See "Evaluation of cardiac risk prior to noncardiac surgery" and "Nonthyroid surgery in the patient with thyroid disease", section on 'Is preoperative measurement of TSH necessary?'.)
RITUXIMAB —
Rituximab is a chimeric monoclonal antibody (mAb) directed against the B cell surface protein CD20. Several biosimilar products have been approved, and we use these interchangeably with rituximab. These antibodies are thought to eliminate B cells via apoptosis, antibody-dependent cytotoxicity, and complement-mediated lysis [30]. Plasma cells responsible for long-term antibody production do not express CD20, which may explain the failure of rituximab to reduce autoantibody production.
Patients and clinicians should be informed about the possible reduced vaccine response. (See 'Vaccinations' above.)
Rituximab evidence for efficacy — As noted above and summarized in the flowchart (algorithm 2), rituximab may be a good choice for an individual who wishes to avoid surgery and prefers not to take a medication for an extended period of time; however, the limited duration of its effect may mandate retreatment or an additional second-line therapy. (See 'Choice of second-line therapy' above.)
Based on data from several large reviews and meta-analyses, the overall efficacy of single-agent rituximab therapy is 40 to 60 percent. The median duration of effect is approximately one year; some individuals may require retreatment, and the impact of rituximab is lost in most patients beyond one year.
●A 2015 meta-analysis of randomized trials that compared rituximab plus standard care versus standard care alone (five trials; 463 patients) found a modest benefit of rituximab in improving platelet counts [31]. A sustained complete platelet count response (platelet count >100,000/microL) at 6 months occurred in 47 percent of patients who received rituximab and 33 percent of controls (relative risk [RR] 1.42, 95% CI 1.13-1.77). A partial response (platelet count above 30,000 to 50,000/microL) occurred in 58 percent of patients who received rituximab compared with 47 percent of controls.
In the trial with the longest follow-up (median, 1.5 years), however, responses with rituximab approached placebo (complete responses in 16 percent of individuals treated with rituximab versus 7 percent treated with placebo at the end of follow-up; RR 2.21, 95% CI 0.72-6.75) [13]. Avoidance of splenectomy (or avoidance of the criteria for splenectomy [platelet count <20,000/microL or need for continued glucocorticoid therapy]) was seen in 81 percent of the rituximab group and 73 percent of the placebo groups. Three late remissions occurred, more than a year after randomization, in patients receiving no therapy.
●A meta-analysis from 2012 that included randomized trials and observational studies in which non-splenectomized individuals were treated with rituximab found an overall response rate of 57 percent and platelet counts >100,000/microL in 41 percent [32].
Although the median duration of response to rituximab (approximately one year) is shorter than splenectomy, some individuals can have long-lasting responses. This was illustrated in a study that evaluated the duration of response in 72 adults who had an initial response to rituximab that lasted for at least one year and 66 children with a response of any duration [10]. After five years of observation, 21 percent of adults and 26 percent of children had a continued response. It is unclear whether these long-lasting responses are attributable to rituximab or whether these cases were destined to have a remission.
Rituximab planning and dosing
●Before starting – Patients should be screened for hepatitis B virus (HBV) infection before starting rituximab because of the risk of HBV reactivation. Rituximab is generally avoided in individuals with active or occult HBV infection; if rituximab must be used, prophylactic anti-HBV treatment against hepatitis B should be considered in consultation with an infectious disease specialist or hepatologist. (See "Hepatitis B virus: Overview of management".)
We check baseline immunoglobulin levels since repeated doses of rituximab can lead to hypogammaglobulinemia. (See "Secondary immunodeficiency induced by biologic therapies".)
Treatment with rituximab can suppress vaccine responses for at least six months after administration. We provide appropriate immunizations before starting rituximab therapy [33]. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.)
COVID-19 vaccination should be updated before starting rituximab. Patients and their doctors are advised to review the latest recommendations regarding booster vaccine doses in patients receiving immunosuppressive therapy. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals' and "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)
●Dose – The dose of rituximab typically used in patients with ITP is 375 mg/m2 intravenously once a week for four consecutive weeks. We favor this dosing based on more extensive experience with it, although lower doses may be sufficient for ITP therapy compared with hematologic malignancies.
Evidence for other dosing:
•1000 mg days 1 and 15 – A study that treated 248 patients with either 375 mg/m2 once a week for four weeks or 1000 mg on days 1 and 15 (choice of regimen based on clinician preference) showed similar efficacy of the two regimens, with initial responses in 152 patients (62 percent and 61 percent) and lasting responses at two years in 96 patients (39 percent and 40 percent) [34]. Another study that treated 108 patients with two fixed doses of rituximab (1000 mg on days 1 and 15) showed a response rate of 44 percent [35].
•100 mg/week for four weeks – A study that treated 48 patients with rituximab at 100 mg/week for four weeks found similar efficacy to higher doses (response in 60 percent, platelet count normalized in 40 percent) [36,37].
●Concurrent therapies – Responses to rituximab can occur within a week but may take up to two months (table 2). Rituximab may be administered with other treatments because its effects on platelet count can be delayed.
Rituximab toxicities — Adverse effects of rituximab include [34]:
●Infusion reactions, which can occur in approximately one-fifth of patients. (See "Rituximab: Principles of use and adverse effects in rheumatologic disease", section on 'Infusion reactions'.)
●Prolonged immunosuppression, which can result in infections (especially in the first six months following treatment) and reactivation of HBV infection. (See "Secondary immunodeficiency induced by biologic therapies".)
●Progressive multifocal leukoencephalopathy (PML) has been rarely reported following rituximab for ITP; many of the affected individuals had been pretreated with other immunosuppressive agents in addition to rituximab [38].
●Reduced response to immunizations.
●Boxed warnings for infusion reactions, hepatitis B reactivation, mucocutaneous reactions, and PML are included in the prescribing information.
These toxicities are discussed in more detail separately. (See "Rituximab: Principles of use and adverse effects in rheumatologic disease", section on 'Adverse effects' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
The mechanisms by which rituximab may cause immunosuppression are discussed separately. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab'.)
TPO RECEPTOR AGONISTS —
Thrombopoietin receptor agonists (TPO-RAs), also called TPO mimetics, include small molecule peptide and non-peptide agents. These act by stimulating the production of megakaryocytes and, ultimately, platelets in the bone marrow by binding to and activating the TPO receptor. (See "Biology and physiology of thrombopoietin".)
Decision to use a TPO-RA — As noted above and summarized in the flowchart (algorithm 2), a TPO-RA may be a good choice for an individual who wishes to avoid surgery and the immunosuppressive effects of splenectomy or rituximab and who is less concerned about the need to take medication for an extended period of time. (See 'Choice of second-line therapy' above.)
Approximately 80 percent of individuals with ITP will have a significant platelet count increase in response to a TPO-RA [39,40]. Several reports have documented sustained responses in some individuals with ITP after discontinuation of a TPO-RA, with response rates up to 30 percent, although observation periods have been relatively short (<1 year) [41,42]. In most individuals, these agents do not induce remission, and prolonged maintenance therapy is usually required. If treatment is discontinued, platelet counts generally return to baseline levels or even below baseline ("rebound thrombocytopenia").
Choice of TPO-RA — Available TPO-RAs for ITP in the United States include romiplostim, eltrombopag, and avatrombopag. They are all effective, but they have not been compared head-to-head in randomized trials. The 2019 American Society of Hematology (ASH) guideline (which did not consider avatrombopag data) does not express a preference for one TPO-RA and suggests a choice based on patient preferences for the route of administration [1]. We individualize their selection based on availability, cost, patient comorbidities, and patient preference. Some individuals strongly prefer one administration route (oral or subcutaneous) over the other.
●Romiplostim – Romiplostim (Nplate) is administered as a once-weekly subcutaneous injection. It is a recombinant protein that contains a peptide with four binding sites for the TPO receptor linked to an IgG1-Fc component, termed a "peptibody" [43-45]. (See 'TPO-RAs dosing and monitoring' below.)
●Eltrombopag – Eltrombopag (Promacta, Revolade) is a once-daily pill. It is a non-peptide small molecule that activates the TPO receptor. Eltrombopag should be dose-reduced or avoided in patients with liver disease or increased liver enzymes. Dose reductions are recommended for patients of East Asian descent. The prescribing information includes a Boxed Warning regarding risks of hepatic decompensation in individuals with chronic hepatitis taking ribavirin or interferon and risks of hepatotoxicity. It is taken without food or with food low in calcium. (See 'TPO-RAs dosing and monitoring' below.)
●Avatrombopag – Avatrombopag (Doptelet; approved for ITP in 2018) is a once-daily pill. It is a non-peptide small molecule that activates the TPO receptor at the same location as eltrombopag. It can be taken with food and has good bioavailability. (See 'TPO-RAs dosing and monitoring' below.)
TPO-RAs may not be an option due to cost and lack of availability.
Recombinant human TPO is used in China; however, it has limited or no availability in most jurisdictions [46,47]. (See "Clinical applications of thrombopoietic growth factors", section on 'Recombinant thrombopoietins'.)
TPO-RAs dosing and monitoring — TPO-RAs are titrated to keep the platelet count in a safe range (typically ≥50,000/microL) without causing thrombocytosis. Dosing starts with a low initial dose that is adjusted as needed, and the platelet count is closely monitored until a stable dose is reached.
●Dosing
•Romiplostim – Subcutaneous injection once weekly. Typical starting dose is 1 mcg/kg up to 3 to 4 mcg/kg, depending on the patient weight and vial size. Most patients in the clinical trials required 3 to 8 mcg/kg (range from 1 to 10 mcg/kg) [48,49].
Vials contain either 250 mcg or 500 mcg of the drug, which would equal approximately 3 mcg/kg or 6 mcg/kg for an 80 kg patient [48].
•Eltrombopag – Oral pill once daily. Polyvalent cations reduce absorption; eltrombopag should be taken without a meal or with a meal low in calcium (≤50 mg) and at least two hours before and four hours after calcium-containing foods, medications such as antacids, and supplements containing polyvalent cations such as calcium, iron, aluminum, magnesium, selenium, or zinc.
The initial dose is 50 mg once daily; an initial dose of 25 mg once daily is used in individuals of East-Asian ancestry (Chinese, Japanese, Korean, Taiwanese) and individuals with moderate or severe liver insufficiency [50].
Eltrombopag inhibits the transporter OATP1B1, which is responsible for transporting certain drugs, such as rosuvastatin. Patients should be monitored closely for toxicities of OATP1B1 substrates, and/or they may decrease the dose of these drugs.
•Avatrombopag – Oral pill once daily, taken with food. There are no interactions with dairy products or other medications and there is no known hepatotoxicity.
●Platelet count monitoring – For all of these agents, platelet counts increase in approximately 7 to 14 days (table 2) [51].
To avoid risks of thrombocytosis, we generally check the platelet count:
•Approximately 5 to 7 days after starting therapy
•Approximately one week after dose changes
•Monthly after a stable dose is reached
•If there is a concern about thrombocytopenia (eg, petechiae, mucosal bleeding, intercurrent illness)
●Monitoring liver enzymes – For eltrombopag, liver enzymes should be measured prior to drug initiation and every two weeks during dose adjustments.
●Switching between TPO-RAs – While the efficacy of all of the TPO-RAs are similar, investigators have observed an improvement in platelet counts after switching from one agent to another in some patients. As an example, in an observational study of 44 patients who switched from eltrombopag or romiplostim to avatrombopag, 41 (93 percent) experienced a platelet response (platelet count ≥50,000/microL) [52]. In patients who switched for ineffectiveness of romiplostim or eltrombopag, the platelet count increased from 28,000/microL to 88,000/microL (p = 0.025). A previous study showed that switching from eltrombopag to romiplostim or vice versa could be beneficial in some patients [53].
TPO-RAs efficacy and adverse events — As noted above, TPO-RAs have not been directly compared in individuals with ITP. (See 'Choice of TPO-RA' above.)
The efficacy and toxicities of individual TPO-RAs have been evaluated in various clinical trials such as the following:
●Romiplostim – The efficacy of romiplostim in raising platelet counts is approximately 80 percent, with higher response rates when transient responses are included [54-57]. The following studies illustrate the range of findings:
•A pooled analysis of data from 14 trials involving 1059 patients treated with romiplostim for up to five and a half years found no difference in the rates of thrombosis, hematologic malignancy/dysplasia, or non-hematologic malignancies over that seen in controls [58]. Bone marrow reticulin was seen in 17 of 921 patients receiving romiplostim and 1 of 65 patients receiving placebo (1.8 versus 1.5 percent); an additional romiplostim-treated patient had increased collagen. Other series have reported rates of adverse events in the range of 13 percent, with thrombotic events in the range of 5 to 7 percent [48,58,59].
•An open-label randomized trial from 2010 in 234 patients with ITP found a higher rate of platelet count responses with romiplostim (platelet count >50,000/microL: 71 to 92 percent with romiplostim versus 26 to 51 percent with standard care); the proportion undergoing splenectomy was also lower (9 percent with romiplostim versus 36 percent with standard care) [49]. Serious adverse events occurred in 23 percent of romiplostim-treated patients versus 37 percent of controls.
•A randomized trial from 2008 in 125 adults with ITP found responses to romiplostim in 38 percent of individuals with prior splenectomy and 61 percent without prior splenectomy, versus 0 to 5 percent with placebo [55]. Additional romiplostim-treated patients had transient responses. Response to romiplostim was accompanied by decreased bleeding and improved health-related quality of life as measured by the ITP-Patient Assessment Questionnaire [60].
•A series of 292 adults treated with romiplostim for up to five years found responses in 90 percent [48]. Responses were inversely correlated with the duration of ITP. Overall, 67 percent of patients could avoid using other ITP medications, such as glucocorticoids. Headache was the most common adverse event.
●Eltrombopag – The efficacy of eltrombopag in raising platelet counts is in the range of approximately 80 percent, with higher response rates when transient responses are included [61-63].
•A 2011 trial (RAISE) randomly assigned 197 adults with chronic ITP and platelet count <30,000/microL to eltrombopag or placebo and found platelet count responses in 79 percent of eltrombopag-treated patients (versus 28 percent with placebo) [62]. Durable responses occurred in 51 percent of individuals who had previously undergone splenectomy and 66 percent who had not (versus 10 percent of controls). Clinically significant bleeding was reduced (33 percent, versus 53 percent with placebo).
•The 2013 EXTEND study followed 299 patients treated with eltrombopag for up to three years. Responses were seen in 80 and 88 percent of patients with and without splenectomy, and responses were maintained (with continued administration of eltrombopag) for approximately 70 percent of the study duration [63]. A follow-up of EXTEND published in 2017 reported that the median duration of eltrombopag was approximately 2.4 years, and 259 of 302 patients (86 percent) had a platelet count >50,000/microL at least once [64]. Adverse events leading to withdrawal (hepatobiliary changes, cataracts, thrombosis, headache, myelofibrosis) occurred in 41 (14 percent), but rates of hepatobiliary and thromboembolic events did not increase with treatment duration beyond one year.
•In a 2011 trial that included 197 patients, 17 of 135 (13 percent) discontinued therapy because of adverse events, the most common of which were liver enzyme abnormalities (four patients) and thromboembolic events (two patients) [62]. There were no significant differences in the development of cataracts or malignancies in the eltrombopag and placebo groups. Additional studies have not demonstrated other safety concerns [48,63,65,66].
●Avatrombopag – Avatrombopag was approved by the US Food and Drug Administration in 2018.
•In a 2014 trial in 64 adults with chronic ITP (relapsed or unresponsive to first-line therapy), avatrombopag showed a dose-dependent increase in platelet counts (percentage of individuals with a response: 0 responses with placebo, 13 percent with 2.5 mg daily, 53 percent with 5 mg daily, 50 percent with 10 mg daily, and 80 percent with 20 mg daily) [67]. Four individuals had thromboembolic events; most had other risk factors for thromboembolic disease.
•In a trial from 2018 in 49 adults with chronic ITP and platelet counts <30,000/microL, avatrombopag at 20 mg daily resulted in a greater duration of sustained platelet count ≥50,000/microL than placebo (median, 12.4 versus 0 weeks) [68]. There was a very high dropout rate attributed to lack of a platelet count response, especially in the placebo group, in which only 1 of 17 completed the full trial. Rates of bleeding and use of rescue medications were similar between groups when adjusted for the difference in length of participation. There were four thromboembolic events; three individuals were reported to have risk factors for thromboembolism.
•Preclinical studies in animals suggested that excessively high doses of avatrombopag might cause carcinoid tumors related to changes in gastrin levels; however, in clinical trials, gastrin levels were normal and no clinical issues were seen [69].
Most studies have demonstrated minimal serious adverse events even after administration of these agents for extended periods of time [48]. However, concerns related to the following potential toxicities have been raised:
●Thrombosis – All TPO-RAs have been associated with a small increased risk of thrombosis in some populations. However, results from a 2015 meta-analysis that included romiplostim and eltrombopag suggest that the risk of thrombosis was not increased in patients with ITP [70]. Smaller studies with avatrombopag suggest that thrombosis is not a risk with short-term treatment, but there are insufficient data to determine the actual risk [71].
●Bone marrow reticulin – Initial concerns were raised regarding the possibility of increasing bone marrow reticulin formation with romiplostim and eltrombopag; however, this was not demonstrated in follow-up studies [58]. We do not monitor bone marrow fibrosis in individuals receiving a TPO-RA, as there is no evidence of progression to myelofibrosis or that serial bone marrow testing leads to improved outcomes. In a romiplostim study using bone marrow surveillance of 131 biopsies, nine (7 percent) demonstrated increases of reticulin and collagen of ≥2 grades on the modified Bauermeister scale after one to three years of treatment [72]. Three of the nine patients had repeat biopsies after stopping the drug that showed resolution of the abnormalities. In an eltrombopag study with 5.5 years of follow-up, moderate reticulin fibrosis of the bone marrow was seen in 2 of 117 patients (1.7 percent) [73].
●Antibodies – These agents have no sequence homology to thrombopoietin and are not expected to generate inhibitory antibodies.
These issues and potential toxicities in patients with other underlying conditions (eg, theoretical risk of hematologic malignancy in patients with myelodysplasia) are discussed in more detail separately. (See "Clinical applications of thrombopoietic growth factors", section on 'Side effects and risks'.)
FOSTAMATINIB —
Fostamatinib (also called fostamatinib disodium or fostamatinib disodium hexahydrate) was approved by the US Food and Drug Administration (FDA) in mid-2018 for the treatment of thrombocytopenia in adults with chronic ITP who have had an insufficient response to a previous treatment [74].
Fostamatinib is a small molecule prodrug of a tyrosine kinase inhibitor that inhibits Syk (spleen tyrosine kinase). The major metabolite of fostamatinib, R406, is active in Syk inhibition. R406 is thought to increase the platelet count in patients with ITP by reducing phagocytosis and destruction of autoantibody-coated platelets by macrophages via inhibition of signal transduction through Fc-activating receptors and the B-cell receptor [74,75].
Decision to use fostamatinib — Fostamatinib is a good choice for individuals who wish to avoid immunosuppression and surgery. Since fostamatinib does not increase the thrombosis rate, it may also be a good choice for individuals who have a higher-than-average thrombosis risk.
In some regions, fostamatinib is the only non-immunosuppressive therapy available, due to a lack of access to TPO-RAs.
Fostamatinib dosing and monitoring
●Dosing – The initial dose for fostamatinib is 100 mg orally twice daily, which can be increased to 150 mg twice daily if the platelet count has not increased to at least 50,000/microL after one month [74].
●Monitoring – The following should be monitored:
•Complete blood count (CBC) including platelet count is checked monthly until stable.
•Liver function tests are checked monthly.
•Blood pressure is checked every two weeks until a stable monthly dose is reached.
Dose escalations or reductions, drug discontinuation, or other therapies (eg, antihypertensive or antiemetic medications) may be required. Like TPO-RAs, fostamatinib is expected to be a maintenance treatment that must be continuously administered to maintain a safe platelet count.
Fostamatinib efficacy and adverse events
●Efficacy – Response rates are good but generally require continued administration.
•In a 2024 meta-analysis of observational studies and randomized trials (11 studies, 722 patients), the overall response rate with fostamatinib was 70 percent; 28 percent had stable responses [6].
•In two randomized trials (FIT-1 and FIT-2) from 2018, which together randomly assigned 150 individuals with chronic ITP (median duration, 8.5 years; median platelet count, 16,000/microL) to receive fostamatinib or placebo, fostamatinib was associated with a greater rate of stable platelet count >50,000/microL (18 versus 2 percent; p = 0.0003) [76]. Forty-four individuals assigned to placebo underwent crossover to fostamatinib (FIT-3 study), and 10 (23 percent) also had a platelet count response. The median time to respond was approximately two weeks. In the subgroup of 32 patients who received fostamatinib as true second-line therapy (after receiving only one prior therapy), the overall response rate was 75 percent [77]. Among the entire group, severe and serious bleeding events were reduced with fostamatinib (5 versus 16 percent) [76]. The most common adverse events were diarrhea, hypertension, nausea, dizziness, and an increase in alanine aminotransferase (ALT); less common adverse events included neutropenia and rash. In an open-label extension study, participants in FIT-1 and FIT-2 were followed over a longer duration; stable responses with a median duration of >28 months occurred in 18 percent [78].
Many fostamatinib-treated patients who had a response had previously tried other treatments that were not effective, including splenectomy and thrombopoietin receptor agonists (TPO-RAs). In the FIT trials, patients had tried at least one prior therapy, and most had tried multiple (median, 3; range, up to 13) [76].
●Adverse effects – Side effects of fostamatinib include diarrhea (31 percent, versus 15 percent with placebo), nausea (19 percent, versus 8 percent with placebo), hypertension, neutropenia, and rash [76,78]. Most of these are mild and resolve with dose reductions and/or appropriate treatments.
OTHER THERAPIES —
For patients for whom the therapies discussed above are ineffective, not well tolerated, or unavailable, management may be more complex, and a hematologist with experience in managing patients with ITP should be involved in the treatment decisions.
Several options are available, as discussed in the following sections. Choices among these therapies vary according to clinician and patient preference, and it may take time to find the best agent for each patient.
Immunosuppressive agents — Immunosuppressive agents other than glucocorticoids at the standard dose and schedule have been used to treat ITP, with case reports or small, uncontrolled series describing successful use [21]. However, these case series often included patients with mild short-term thrombocytopenia (ie, possibly not ITP) or had only a minority of patients with ITP unresponsive to splenectomy, rituximab, or a TPO-RA [79].
●Intermittent glucocorticoids – Although glucocorticoids are highly effective as initial therapy, we generally avoid long-term continuous and intermittent glucocorticoids due to toxicities with extended use and availability of other good options. An exception is the uncommon patient who is able to maintain a safe platelet count on very low-dose glucocorticoids (eg, prednisone at a dose of ≤5 mg/day). (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Glucocorticoids and IVIG'.)
We sometimes use low-dose intermittent glucocorticoids in patients with a platelet count response. For example, some patients maintain a safe platelet count on oral prednisone at doses as low as 5 or 10 mg every other day. However, even these low doses can accelerate the development of osteoporosis and other glucocorticoid toxicities [80-82]. (See "Major adverse effects of systemic glucocorticoids".)
●MMF – A study involving 46 individuals with severe ITP reported disease responses to mycophenolate mofetil (MMF) in 24 (52 percent); 15 had platelet counts over 100,000/microL [83]. The standard dose was 1 g daily. MMF has also been used in combination regimens. It is generally well tolerated and, in many jurisdictions, is available as a generic formulation that is less expensive than other therapies. (See 'Combinations' below and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Other therapies and multi-agent combinations'.)
●Azathioprine – A series of 53 individuals with chronic ITP that persisted despite other therapies (splenectomy in 40) reported success with azathioprine at an initial oral dose of 150 mg/day; in some cases, several months of therapy were needed before a response was seen [84]. Thiopurine methyltransferase (TPMT) testing should be performed in all patients initiating azathioprine.
●Cyclosporine – Therapies used by other clinicians in extreme circumstances with reports of success have included cyclosporine, vincristine, and cyclophosphamide, alone or in combination, and hematopoietic stem cell transplant [85-90].
●Daratumumab – A report of seven individuals with refractory ITP treated with daratumumab described four responses, all with continuous remission lasting months to years [91]. Implications of daratumumab for crossmatching for red blood cell (RBC) transfusion are discussed separately. (See "Red blood cell (RBC) transfusion in individuals with serologic complexity", section on 'Anti-CD38 (daratumumab, isatuximab)'.)
●Intravenous immune globulin (IVIG) – We consider IVIG a rescue treatment in ITP rather than routine, ongoing therapy. IVIG is important for patients with clinically important bleeding and for patients in whom a more rapid response is required [21]. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'IVIG dosing and administration'.)
Danazol and dapsone
●Danazol – Danazol is an attenuated androgen that may be effective for ITP. Danazol is generally well tolerated in males, but hirsutism can be a troubling side effect for females. In uncontrolled case series, platelet count responses to initial oral doses of 600 mg/day have been reported in up to 72 percent of patients [92-94]. Its efficacy in patients with chronic refractory ITP is unknown and may be limited [21,95].
●Dapsone – A series of 122 individuals treated in a referral center with dapsone reported responses in 81 (66 percent) [96]. The starting dose was 100 mg daily; higher doses did not improve the response rate. The cohort mostly consisted of individuals with chronic ITP, although some were treated with dapsone as their initial ITP therapy. Complete responses were seen in 29 (24 percent), with sustained responses in approximately one-half. Mild elevations in methemoglobin were common, with symptomatic methemoglobinemia in five individuals. Dapsone may cause oxidative hemolytic anemia. (See "Methemoglobinemia", section on 'Dapsone' and "Drug-induced hemolytic anemia", section on 'Oxidant injury'.)
Combinations — In some patients who require therapy because of severe and symptomatic thrombocytopenia unresponsive to single agents, combinations of agents may be effective. The rationale for giving a combination of therapies includes the need for more rapid effects of the faster-acting agents until the more durable effects of longer-acting agents take effect and the possibility of synergism between different agents [97].
Combinations that have been tested include:
●Various combinations with a TPO-RA, especially with an agent that inhibits platelet clearance, such as fostamatinib, rituximab, or a glucocorticoid [98].
●Triple therapy given over four weeks (TT4) using high-dose oral dexamethasone (40 mg daily on days 1 to 4), oral cyclosporine (2.5 to 3 mg/kg daily on days 1 to 28) and low-dose rituximab (100 mg on days 7, 14, 21, and 28) [99].
●Azathioprine, MMF, and cyclosporine [100].
●Glucocorticoids, IVIG, vincristine, and/or anti-D was administered to 35 patients whose disease did not respond to single-agent glucocorticoids, IVIG, or splenectomy, with or without azathioprine and danazol [101].
●Glucocorticoids, cyclophosphamide, and vincristine, procarbazine, or etoposide [102].
●All-trans retinoic acid (ATRA) with low dose rituximab [103].
For the most part, adverse events in these studies have been considered tolerable, but they are generally greater than seen in patients treated with single agents [99-102,104,105].
INVESTIGATIONAL THERAPIES
Rilzabrutinib (investigational BTK inhibitor) — Rilzabrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor under investigation for several immune-mediated disorders.
In a 2025 trial (LUNA2, part B) that treated 26 patients with refractory ITP (median platelet count: 13,000/microL; median duration of ITP: 10 years; median number of prior therapies: six), rilzabrutinib 400 mg twice daily for 24 weeks resulted in responses (platelet count ≥50,000/microL or double baseline and ≥30,000/microL) in nine participants (35 percent) [106]. Among 11 individuals who participated in a long term extension study, platelet counts were >80,000/microL. Treatment related adverse events for the entire group included diarrhea (35 percent), headache (23 percent) and nausea (15 percent). There were no serious bleeding or thrombotic complications.
An earlier open-label dose-finding study in 60 patients with ITP and platelet count <30,000/microL not responsive to other therapies (median duration of ITP: six years; median number of prior therapies: four), platelet count responses to rilzabrutinib were seen in 24 (40 percent), with a median time to platelet count response of 12 days [107]. Treatment-related adverse events (all mild) included nausea, diarrhea, and fatigue. Some patients who continued therapy beyond one year had durable responses [108].
Increased specificity of rilzabrutinib reduces the risk of off-target effects such as atrial fibrillation.
Other BTK inhibitors can cause bleeding by inhibiting platelet aggregation, but rilzabrutinib does not appear to have this effect.
Efgartigimod (FcRn inhibitor) — Efgartigimod reduces the levels of anti-platelet autoantibodies that may contribute to the pathophysiology of ITP; it does so by acting as a decoy for the neonatal Fc receptor (FcRn), in turn preventing FcRn from stabilizing circulating IgG [109]. It is approved or under investigation for various autoantibody and alloantibody-mediated conditions.
In a 2023 randomized trial involving 131 adults with chronic or persistent ITP and platelet count <30,000/microL, efgartigimod 10 mg/kg intravenously was more effective than placebo in raising the platelet count above 50,000/microL (22 versus 5 percent) [110]. The patients had longstanding ITP, with a mean of 10.6 years since diagnosis; two-thirds had received at least three prior ITP therapies, and slightly over one-third had a splenectomy. Therapy was well-tolerated, but regular intravenous infusions (once weekly or every other week) are required.
Sutimlimab (monoclonal antibody against complement component C1s) — Sutimlimab is used to reduce hemolysis in cold agglutinin disease. (See "Cold agglutinin disease", section on 'Anti-complement therapies'.)
Sutimlimab and other complement inhibitors are under study for ITP [111-113].
Anti-CD38 — CD38 is a cell surface protein on various hematopoietic cells (plasma cells, hematopoietic stem cells). (See "Normal B and T lymphocyte development", section on 'Plasma cells' and "Overview of hematopoietic stem cells", section on 'Cell surface antigenic markers'.)
A study administered CM313, an anti-CD38 monoclonal antibody, to 22 patients with persistent or chronic ITP; dosing was once weekly intravenous for 8 weeks, followed by 16 weeks of observation [114]. Patients had received a median of four prior ITP therapies. Responses, defined as platelet count ≥50,000/microL on at least two occasions, were seen in 21 patients (95 percent). By week 24, sustained responses were seen in 14 of 21 (67 percent); one patient died of intracranial hemorrhage the day after the first infusion, not considered drug-related. Therapy was well-tolerated in the remaining 21 patients, although one-third had an infusion reaction.
CAR-T cells — Case reports have described the use of chimeric antigen receptor (CAR-T) cells in patients with lupus-associated or multi-refractory ITP [115,116].
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".)
SUMMARY AND RECOMMENDATIONS
●Patients with bleeding – Treatments for acute, severe bleeding or urgently needed platelet count increases for surgery or obstetric indications in individuals with immune thrombocytopenia (ITP) are discussed separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Critical or severe bleeding' and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Surgery or delivery'.)
●Threshold for therapy – The goal of treatment in ITP is to provide a safe platelet count to prevent clinically important bleeding. We often initiate second-line treatment at a lower platelet count (<20,000/microL) than first-line therapy (<30,000/microL) (algorithm 1). Therapy is more important for patients with a higher risk of bleeding (comorbidities such as chronic kidney disease, concomitant antithrombotic agents, and athletic activities). (See 'Initial considerations' above and "Initial treatment of immune thrombocytopenia (ITP) in adults".)
●Before starting – Consider other possible diagnoses such as inherited platelet disorders, myelodysplastic syndrome, consumptive coagulopathies, and drug-induced thrombocytopenia. Evaluate for treatable causes of secondary ITP, such as Helicobacter pylori infection, HIV infection, hepatitis C virus (HCV) infection, large granular lymphocyte disorders, chronic inflammatory disorders or chronic lymphocytic leukemia (CLL). Provide appropriate vaccinations before immunosuppressive therapy (rituximab or splenectomy). (See 'Initial considerations' above.)
●Choice of second-line therapy – The principal options are splenectomy, rituximab, a thrombopoietin receptor agonist (TPO-RA), or fostamatinib. These differ in mechanism of action, efficacy, administration, and adverse effects; the choice is individualized. We discuss the risks and benefits of all options (table 1) and assist the patient in arriving at a decision consistent with their values and preferences (algorithm 2). We avoid chronic use of intravenous immunoglobulin (IVIG), except in special circumstances, given its costs, complexity of administration, potential side effects, and transient effectiveness.
•Splenectomy – May be preferable for an individual who wishes to have a potentially curative procedure (response rate, 80 to 90 percent), avoid regular medication, and accept risks of immunosuppression and venous thromboembolism (VTE). Predictors of efficacy include younger age and splenic sequestration on radiolabeled liver-spleen scans (not used routinely in the United States). The laparoscopic approach carries lower surgical morbidity and mortality. (See 'Splenectomy' above.)
-We often wait at least 12 months to allow late remissions.
-We provide preoperative immunizations.
-A minimally invasive approach is expected to have a shorter hospital stay and lower rate of surgical complications. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Open versus minimally invasive procedure'.)
•Rituximab – May be preferable for an individual who wishes to avoid surgery, prefers not to take medication for an extended duration of time, and accepts risks of immunosuppression and need for retreatment. Efficacy is 40 to 60 percent; median duration of response is approximately one year. Long-term efficacy is similar to placebo; some individuals may require retreatment. (See 'Rituximab' above.)
-We provide immunizations and test hepatitis B virus (HBV) serologies before administration.
-The optimal dose is unknown; many clinicians use 375 mg/m2 intravenously once weekly for four weeks.
•TPO-RA – A TPO-RA may be preferable for an individual who wishes to avoid surgery and immunosuppression and is less concerned about the costs and burdens of daily or weekly medication. Some individuals strongly prefer oral or subcutaneous administration. Adverse effects include thromboembolism and bone marrow fibrosis (reversible). Close platelet count monitoring is used to avoid thrombocytosis. Eltrombopag requires liver enzyme testing. (See 'TPO receptor agonists' above.)
-Romiplostim – Weekly subcutaneous injection
-Eltrombopag – Oral daily pill taken without polyvalent cations
-Avatrombopag – Oral daily pill taken with food
•Fostamatinib – May be preferable for an individual who wishes to avoid surgery and immunosuppression, especially if a TPO-RA is not available, and who is willing to take a twice-daily medication. (See 'Fostamatinib' above.)
●Other therapies – Include other immunosuppressive agents, danazol, dapsone, and combinations. Choices are individualized; it may take time to find the best approach for each patient. Additional therapies are under investigation. (See 'Other therapies' above and 'Investigational therapies' above.)
●Children and pregnancy – (See "Immune thrombocytopenia (ITP) in children: Management of newly diagnosed patients" and "Immune thrombocytopenia (ITP) in children: Management of patients with persistent, chronic, or refractory disease" and "Thrombocytopenia in pregnancy", section on 'Immune thrombocytopenia (ITP)'.)
●Diagnosis and initial therapy – (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis" and "Initial treatment of immune thrombocytopenia (ITP) in adults".)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges James N George, MD, who contributed to many earlier versions of this topic review.
