Approach

Treatment modalities and goals should be individualized, based on the phase of immune thrombocytopenia (ITP), bleeding symptoms and risk, and patient preferences.

Asymptomatic patients may not need treatment and are often managed with close observation. For newly diagnosed patients with bleeding symptoms, corticosteroids are the standard initial treatment; intravenous immune globulin (IVIG) and intravenous Rho(D) immune globulin are also first-line options. Subsequent treatment options for persistent or chronic ITP may include a thrombopoietin receptor agonist, rituximab, or fostamatinib (adults only). Splenectomy may be an option from 12 months after diagnosis. Patients presenting with severe, life- or organ-threatening bleeding require emergency treatment with corticosteroids, IVIG, and platelet transfusion.

Patients should have sufficient platelet levels before undergoing any type of procedure or surgery. Guidelines provide recommendations for target platelet levels for dental procedures and surgery in adults (e.g., minor surgery ≥50 × 10³/microliter, major surgery ≥80 × 10³/microliter).[15]​ See Criteria.

Emergency treatment for adults and children

All adults and children with life- or organ-threatening bleeding, regardless of platelet count, require emergency treatment with a combination of platelet transfusion, a corticosteroid (e.g., prednisone, methylprednisolone, or dexamethasone), and IVIG. A life- or organ- threatening ITP bleed may be at an anatomical site (e.g., intracranial, intraspinal, intraocular, retroperitoneal, pericardial, or intramuscular with compartment syndrome) or a bleed that results in hemodynamic instability or respiratory compromise.[30]

Emergency treatment may take 1-5 days to have an effect, and usually lasts for 2-4 weeks, whether or not the patient has had a prior splenectomy.

Although platelets are likely to be rapidly destroyed during transfusion, there is evidence to suggest that patients with active bleeding respond transiently to transfusion.[31] IVIG can prolong platelet survival; therefore, platelet transfusion may be more effective if given after IVIG infusion.[32]​ Patients may respond to repeated doses, but this response can diminish over time.

The antifibrinolytic agents aminocaproic acid and tranexamic acid inhibit fibrinolysis and can help stabilize clots that have already formed. These agents can be used as adjunctive treatment as they do not affect platelet count. However, they are contraindicated in patients with hematuria as clots in the collecting system of the kidneys can lead to outlet obstruction.

Thrombopoietin receptor agonists do not act quickly enough to have a role in initial emergency treatment, but they may be considered as a subsequent treatment option if the response to emergency treatment is inadequate, or they may be considered as a concurrent treatment to provide longer-lasting benefit and prevent relapse.[15][33][34]​​​

Initial treatment in newly diagnosed adults

The decision to treat should be individualized, taking into account severity of bleeding symptoms, risk of bleeding, risk of side effects from treatment, age, comorbidities, use of antithrombotic medications, lifestyle, and patient preference.[15][35]​​​ Asymptomatic patients do not typically require immediate treatment.[35] However, some patients with a very low platelet count may experience minimal symptoms. Risk of bleeding increases at platelet levels <20 × 10³/microliter, so a platelet count of 20-30 × 10³/microliter is generally chosen as a threshold for treatment in adults.​[15][35]​​ For patients with a platelet count >30 × 10³/microliter, the risks of morbidity from treatment should be carefully weighed against the potential benefits.[36]

Adults with platelet count ≥30 × 10³/microliter:

  • Asymptomatic adults (or those with only minor mucocutaneous bleeding) who have no additional risk factors do not require immediate treatment; close observation is advised. Clinical follow-up and platelet count are required if bleeding symptoms develop, or prior to surgery or dentistry.

  • Adults with bleeding symptoms and/or additional risk factors can be treated first-line with a corticosteroid, IVIG, or intravenous Rho(D) immune globulin, as for adults with platelet count <30 × 10³/microliter.

  • Risk factors may include antithrombotic treatment, requiring an intervention that may cause bleeding, age >60 years, or an occupation or activities with high risk of injury.

Adults with platelet count <30 × 10³/microliter:

  • Patients generally require treatment due to bleeding symptoms or increased risk of bleeding. Corticosteroids, IVIG, and intravenous Rho(D) immune globulin are considered first-line treatments.

  • Corticosteroids act against the immune-mediated destruction of platelets in ITP, and they are typically the standard initial treatment. Guidelines recommend a short course (≤6 weeks including treatment and taper) of prednisone or dexamethasone.[15][35]​​ Generally, patients will show a response within the first 2-3 weeks of corticosteroid therapy. Stopping or tapering corticosteroid treatment too quickly may result in relapse. Prolonging full dose after 4 weeks does not increase the response rate and may cause corticosteroid-related complications.

  • IVIG can be used if corticosteroids are contraindicated or not tolerated. If a rapid increase in platelet count is required, IVIG can be given in combination with a corticosteroid.

  • Patients who are rhesus (Rh)-positive and nonsplenectomized may benefit from intravenous Rho(D) immune globulin.[37]​ Intravenous Rho(D) immune globulin can be used first-line in these patients, but treatment response may be transient.[37] Patients develop mild, self-limited hemolysis with this agent, and there is a small risk of severe hemolytic complications, but these are rare.[38][39] Immediate anaphylactic reactions and hypersensitivity reactions also occur rarely; chills, fever and headaches are more common. Premedication with a corticosteroid may reduce side effects.[15]

The goal of initial treatment is to rapidly obtain a safe platelet count to prevent or stop hemorrhages, and to ensure an acceptable quality of life with minimal treatment-related toxicities. Around 20% to 30% of patients who have initial treatment will not require further therapy.

Treatment in adults with persistent or chronic disease

ITP in adults is often a chronic disease. Spontaneous remission occurs in around 5% to 10% of cases.[40] ITP (i.e., platelet count ≤100 × 10³/microliter) that does not resolve spontaneously or respond to first-line treatment is defined as:[1]

  • Persistent ITP if duration is 3-12 months after diagnosis.

  • Chronic ITP if duration is beyond 12 months after diagnosis.

However, the clinical relevance of these definitions is contentious, and subsequent treatment should be individualized.

Some patients with persistent or chronic disease respond to first-line treatments (e.g., corticosteroids and/or IVIG), but they require continuous treatment to achieve a platelet count that is safe. However, prolonged courses of corticosteroids (>6 weeks) are not recommended.[15][35]​​

Patients who do not respond to first-line treatment or relapse when corticosteroids are reduced or stopped may be offered a thrombopoietin receptor agonist, rituximab, or fostamatinib as second-line treatment options.

Thrombopoietin receptor agonists:

  • Romiplostim, eltrombopag, and avatrombopag are approved for second-line use in chronic ITP. None of these agents shares sequence homology with endogenous thrombopoietin.

  • Randomized placebo-controlled trials have shown that each of these agents is effective in increasing platelet count (>50 × 10³/microliter) in patients with chronic ITP that was unresponsive or relapsed after one or more treatments, including splenectomy (response rates at 1 month >65% for each agent).[35][41][42][43][44][45]​​​​ [ Cochrane Clinical Answers logo ] ​​​​​ Reduction or discontinuation of concurrent ITP treatment, and reduction of bleeding, and improvement in health-related quality of life were also reported. Long-term safety and efficacy have been demonstrated for romiplostim and eltrombopag.[46][47][48]​​

  • Initial concerns about thrombotic risk, bone marrow reticulin increase, and the potential for promoting neoplasia have lessened.[49]​ However, rebound thrombocytopenia can be a significant problem with romiplostim if doses are missed. 

  • In cases of treatment failure or intolerance to one agent, switching to a different thrombopoietin receptor agonist may be effective.[50]​ One retrospective study showed that switching to avatrombopag was effective following inadequate or poorly tolerated treatment with romiplostim or eltrombopag (93% response rate).[51]

  • Thrombopoietin receptor agonists often require indefinite continuous administration as platelet counts tend to return to basal levels after stopping treatment; however, limited data suggests a response can be sustained in 20% to 30% of patients.[50] A dose-reduction regimen and possible discontinuation may be considered in patients who achieve sustained platelet counts >100 × 10³/microliter and no bleeding for at least 12 months; however, evidence to support this approach is not yet well developed.[52]

  • Differences in administration, dietary interactions, and side effects may affect the choice of thrombopoietin receptor agonist. Romiplostim is given weekly by subcutaneous injection. Eltrombopag and avatrombopag are daily oral treatments (although avatrombopag may be administered less frequently in certain patients as part of dose titration). Eltrombopag needs to be taken at least 2 hours before or 4 hours after consuming products containing polyvalent cations (e.g., antacids and dairy products). Treatment with eltrombopag results in hepatotoxicity in approximately 10% of patients, so monthly liver function testing is required. Eltrombopag is an iron chelator, so ferritin and transferrin saturation monitoring may be required for patients with risk factors for iron deficiency (including menstruation).[52]

Rituximab:

  • Rituximab is a monoclonal antibody that targets CD20 (a B-cell marker). It has a response rate of approximately 60% in adult patients with ITP.[35]​​[53][54][55]​ Durable response rates are lower for rituximab (39.4%) than for thrombopoietin receptor agonists (63.2%) at 6 months.[35]

  • There have been concerns about increased risk of progressive multifocal leukoencephalopathy with rituximab treatment.[56]​ However, this appears to be extremely rare.[57]​ Subsequent studies have reported an acceptable safety profile when used for ITP.[58]​ Risk of infection is increased, and premedication with a corticosteroid is recommended to prevent acute infusion reactions. Repeated use of rituximab may cause hypogammaglobulinemia.[15]

  • Rituximab is contraindicated in patients with active hepatitis B infection because of increased risk of hepatitis B virus reactivation. Patients should be tested for hepatitis B infection before use. Prophylactic antiviral medication and DNA monitoring are required in patients receiving rituximab who have evidence of previous hepatitis B infection. Vaccination may be ineffective in patients treated with rituximab; ideally vaccinations should be given before treatment with rituximab or at least 6 months after the final dose.[15][59]

  • Rituximab is used off-label for ITP.

Fostamatinib:

  • Fostamatinib is a spleen tyrosine kinase (Syk) inhibitor approved for second-line use in chronic ITP.

  • In two parallel 24-week randomized controlled trials involving adult patients with persistent or chronic ITP who were unresponsive to previous treatments, a stable response (defined as a platelet count ≥50 × 10³/microliter for ≥4 of 6 biweekly visits, weeks 14-24, without rescue therapy) was achieved in 18% of patients receiving fostamatinib compared with 2% receiving placebo.[60] Most of these patients had received 3 or more previous therapies, and 80% of participants had a duration of ITP of >2 years (median 8.4 years). A post hoc analysis comparing patient subgroups by line of therapy showed a response rate of 78% when fostamatinib was used as second-line therapy and 48% when used as third- or later-line treatment.[61]

The treatment goal for patients with persistent or chronic disease is to increase platelet count to control clinically relevant bleeding or minimize the risk of major bleeding with minimum toxicity while waiting for spontaneous remission or amelioration. However, improvements become much less likely after 12 months from diagnosis.

In cases of treatment failure or intolerance with one second-line drug, switching to another second-line drug or splenectomy (if 12 months or more after diagnosis) may be considered. If treatment with multiple second-line drugs has failed, the following approaches to salvage therapy may be considered:

  • Immunosuppressant and immunomodulatory drugs: may be attempted as off-label treatments for ITP. These include azathioprine, cyclosporine, cyclophosphamide, danazol, dapsone, and mycophenolate. However, evidence supporting their use is lacking.[15][34]​​ Response to mycophenolate may take several weeks, but it appears to be durable.[62][63][64]​ Vinca alkaloids can be given in the acute setting only. Despite a high response rate (with a generally rapid response), use of vinca alkaloids is limited by severe side effects including peripheral neuropathy that may be irreversible.[15][65]​​

  • Low-dose corticosteroid: may rarely be considered in responsive patients if they can tolerate corticosteroids and they have no contraindications (e.g., diabetes, hypertension, osteoporosis, peptic ulcer). The minimum effective dosage for the shortest time should be used.[15]

  • Repeated IVIG infusions: on-demand treatment may be used for responsive patients if tolerated. Most patients respond initially; however, platelet increase is usually transient. There is a need to be vigilant for potential toxicities associated with repeated IVIG infusions, such as renal failure and thrombosis. Hospital attendance as an outpatient is required.

Splenectomy in adults

Splenectomy is considered a second-line treatment, but it is generally deferred until at least 12-24 months after diagnosis to allow for remission or stabilization of platelet count.[15][35]

The goal of splenectomy is cure or long-lasting remission. A systematic review showed a complete response (i.e., platelet count ≥100 × 10³/microliter for 30 days or longer with no further treatment for ITP) with splenectomy in around 66% of cases.[66] Splenectomy can be considered if first-line treatments have failed and the patient is deemed suitable for surgery. However, the potential risks and benefits of splenectomy and other second-line treatment options (e.g., rituximab, thrombopoietin receptor agonists, and fostamatinib) should be discussed and a shared decision should be made with the patient. Splenectomy has become less common with the introduction of effective second-line drug options.

Patients with preoperative platelet counts >20 × 10³/microliter can safely undergo splenectomy. A corticosteroid, IVIG, or thrombopoietin receptor agonist may be used to increase platelet count to a safer level (e.g., >50 × 10³/microliter) in advance of surgery. In patients with refractory disease who require immediate treatment, splenectomy can be performed if platelet count is ≤20 × 10³/microliter, and even as low as 5 × 10³/microliter, as platelet count can quickly increase following clamping of the splenic artery.

At least 2 weeks prior to splenectomy, patients should be immunized with vaccines against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis.[67][68]​​​​ Local guidance on vaccination pre- and postsplenectomy should be followed.[69] Vaccination may be ineffective for up to 6 months in patients previously treated with rituximab; ideally, vaccinations should be given >6 months before treatment with rituximab or at least 6 months after the final dose.[15][59]​​ Prophylactic antibiotics should be administered for at least 3 years following splenectomy; some recommend lifelong antibiotic prophylaxis.[67][70][71]

Patients who do not respond to splenectomy should be evaluated for an accessory (supernumerary) spleen with radionuclide or magnetic resonance imaging scans, especially if their peripheral blood smear does not show evidence of splenectomy (i.e., Howell-Jolly bodies).

In cases of treatment failure or relapse after splenectomy, a second-line drug may be considered if they have not already been tried.

Treatment in children

ITP is a benign condition for most affected children, and major bleeding (even with prolonged, severe thrombocytopenia) appears to be rare. Most manifestations are limited to the skin.[22] Children often recover spontaneously within weeks or months, with higher rates of spontaneous remission associated with younger age.[72]​ Studies report complete remission within 6 months in approximately 70% of children with ITP.[73][74]​​​​

Observation is recommended for children who are asymptomatic or have minor bleeding symptoms (e.g., bruising, petechiae, purpura) as the majority will attain a safe platelet count within a few days.[15]​ It is important to reduce trauma risk in these patients and avoid any antiplatelet medications (e.g., aspirin and nonsteroidal anti-inflammatory drugs). Frequency of monitoring should be individualized, based on bleeding symptoms, platelet counts, and patient preferences.[15] Clinical follow-up and platelet count are required if bleeding symptoms develop, or prior to surgery or dentistry.

Treatment for children with newly diagnosed ITP is only advised in the presence of major bleeding symptoms (e.g., mucosal bleeding):​[15][22][35]

  • A corticosteroid is the usual first-line treatment. Guidelines recommend a short course of prednisone (no longer than 7 days including tapering). Methylprednisolone or dexamethasone are alternative options.[35]

  • IVIG or intravenous Rho(D) immune globulin can be used first-line if corticosteroids are contraindicated. Rho(D) immune globulin should only be used in patients who are Rh-positive and nonsplenectomized.​​[35][37]​ IVIG or intravenous Rho(D) immune globulin may be considered in preference to a corticosteroid if a rapid response is required for bleeding symptoms.[15]

Rituximab or a thrombopoietin receptor agonist (eltrombopag or romiplostim) should be considered if there is treatment failure or intolerance with first-line treatments. Eltrombopag and romiplostim are licensed for use in children >1 year of age with chronic ITP that is refractory to other treatments; rituximab is used off-label for ITP.

In a systematic review evaluating rituximab for children with ITP, a platelet count >100 × 10³/microliter (complete response) was reported in around 39% of children with ITP, and a platelet count >30 × 10³/microliter (response) was reported in around 68%, with a median response duration of 12.8 months.[75] In a long-term follow-up study, only 26% of children with an initial response to rituximab maintained a treatment-free response after 5 years.[76]

Eltrombopag and romiplostim have been shown in randomized controlled trials to be safe and effective in children ages 1-17 years with persistent or chronic ITP.[77][78][79]​​​​ In these trials, response rates (platelet count ≥50 × 10³/microliter) 62% and 40% were reported for eltrombopag, and 52% for romiplostim.[77][78][79]

One systematic review and meta-analysis comparing thrombopoietin receptor agonists with rituximab in children suggested a similar platelet response rate for each agent. However, more patients maintained a sustainable response with romiplostim, and time to response was lower for eltrombopag and romiplostim (4.75 weeks) than for rituximab (6.75 weeks).[80]

Splenectomy is rarely indicated in childhood ITP. Children with persistent or chronic disease may be candidates for splenectomy if they are unresponsive to, or intolerant of, pharmacologic interventions, and have life-threatening bleeding or substantially impaired health-related quality of life.[15]​ Splenectomy should be delayed for at least 12 months from diagnosis unless immediate treatment is required (e.g., to improve quality of life).

In children undergoing splenectomy, preoperative prophylaxis with IVIG or oral corticosteroids can be considered to increase platelet count to a safe level and reduce the risk of intraoperative bleeding. At least 2 weeks prior to splenectomy, patients should be immunized with vaccines against S pneumoniae, H influenzae type b, and N meningitidis. Local guidance on vaccination pre- and postsplenectomy should be followed.[81]​ Vaccination may be ineffective for up to 6 months in patients previously treated with rituximab; ideally vaccinations should be given >6 months before treatment with rituximab or at least 6 months after the final dose.[15][59]​​​ Prophylactic antibiotics should be administered for at least 3 years following splenectomy; some recommend lifelong antibiotic prophylaxis.[67][70][71]

ITP in pregnancy

Once a diagnosis of primary ITP has been made, the criteria for starting treatment in pregnancy are the same as for nonpregnant patients.[20]​ Some treatments used for ITP should be avoided in pregnancy (e.g., fostamatinib, vinca alkaloids and mycophenolate) while others have uncertain safety (e.g., rituximab, and the thrombopoietin receptor agonists). Pregnant patients should be referred to a specialist team including a hematologist and a gynecologist.

A stable platelet count of 20-30 × 10³/microliter is considered safe during pregnancy until the end of the third trimester when higher levels are needed for delivery. Observation should be considered unless the patient has bleeding symptoms or a procedure is planned.​[15][82]

Initial treatment in pregnancy

If treatment is needed during pregnancy, corticosteroids and IVIG are considered safe first-line treatments:​[15][82]

  • Prednisone is usually given as initial therapy (tapered to minimum effective dose). Dexamethasone is not recommended in pregnancy.[82][83]

  • IVIG can be used if corticosteroids are contraindicated or not tolerated. IVIG can be given in combination with prednisone if the response to prednisone is inadequate, a rapid response is needed, or to prepare for delivery.

Intravenous Rho(D) immune globulin may be safe to use in pregnancy for Rh-positive, nonspenectomized women, but evidence is lacking. A small study showed Rho(D) immune globulin was safe and effective for both mother and fetus in the second and third trimester.[84]​ However, there is an increased risk of hemolysis in both mother and baby.

Treatment of persistent or chronic disease in pregnancy

​Pregnant patients with ITP that is unresponsive to initial prednisone or IVIG should be treated with high-dose methylprednisolone, usually in combination with IVIG and/or azathioprine.[15][85]​​​​ Azathioprine has been safely used in pregnancy for other indications (e.g., systemic lupus erythematosus or renal transplantation).

There is limited data on the safe use of rituximab in pregnancy, and there are some concerns about pregnancy outcomes after maternal exposure to rituximab.[86]​ However, guidelines suggest that rituximab can be considered in pregnancy for very severe cases that have not responded to other treatments.[15]​ Monitoring is required for immunosuppression and infection. Rituximab is used off-label for ITP.

Other immunosuppressive agents, including vinca alkaloids, cyclophosphamide, danazol, and mycophenolate, have been associated with teratogenicity and should not be used.

Thrombopoietin receptor agonists are not currently recommended in pregnancy.

Splenectomy in pregnancy

Splenectomy is rarely performed in pregnant patients; however, if it is required (e.g., for severe refractory disease) and the patient agrees to the procedure, it is best performed early in the second trimester and may be performed laparoscopically.[15][20]

Patients with preoperative platelet counts >20 × 10³/microliter can safely undergo splenectomy. Platelet transfusion may be given to increase platelet count if <20 × 10³/microliter; however, infusions should be carried out with caution as thrombocytosis may occur following splenectomy.

At least 2 weeks prior to splenectomy, patients should be immunized with vaccines against S pneumoniae, H influenzae type b, and N meningitidis.[67][68]​​​ Local guidance on vaccination pre- and postsplenectomy should be followed.[69] Vaccination may be ineffective for up to 6 months in patients previously treated with rituximab; ideally vaccinations should be given >6 months before treatment with rituximab or at least 6 months after the final dose.[15][59]​​ Prophylactic antibiotics should be administered for at least 3 years following splenectomy; some recommend lifelong antibiotic prophylaxis.[67][70][71]​​​

Preparing for delivery

A target platelet count of ≥50 × 10³/microliter is usually recommended for vaginal delivery or cesarean section, which may be achieved with prednisone and/or IVIG. If the response to other treatments is inadequate, a thrombopoietin receptor agonist may be considered, although evidence is lacking.[15]​ See Emerging treatments.

For epidural anesthesia, a target platelet count of ≥80 × 10³/microliter is recommended, although risk is likely to be low in patients with a platelet count of >70 × 10³/microliter.[87]​ If an adequate platelet count has not been achieved and delivery is imminent, platelet transfusion in conjunction with IVIG can be considered.[20]

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