Immune thrombocytopenia

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

all patients (child or adult): with life- or organ-threatening bleeding

1st line – IVIG plus corticosteroid plus platelet transfusion

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1st line –

IVIG plus corticosteroid plus platelet transfusion

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, and intravenous immune globulin (IVIG).

A life- or organ-threatening immune thrombocytopenia 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.

Primary options

immune globulin (human): children and adults: 1 g/kg intravenously as a single dose, a second dose may be given if there is a poor response to initial treatment

-- AND --

prednisone: children: 2-4 mg/kg/day orally given in 3-4 divided doses for 5-7 days, maximum 120 mg/day; adults: 0.5 to 2 mg/kg/day orally for 1-3 weeks followed by a gradual taper, maximum 80 mg/day

methylprednisolone sodium succinate: children: 30 mg/kg intravenously every 24 hours for 3 days, followed by treatment with an oral corticosteroid as clinically indicated, maximum 1000 mg/dose; adults: 1000 mg intravenously every 24 hours for 3 days, followed by treatment with an oral corticosteroid as clinically indicated

dexamethasone: children: 0.6 mg/kg orally once daily for 4 days, may repeat course, maximum 40 mg/day; adults: 40 mg orally once daily for 4 days, may repeat course

2nd line – thrombopoietin receptor agonist

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2nd line –

thrombopoietin receptor agonist

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

Primary options

eltrombopag: children 1-5 years of age: 25-75 mg orally once daily, adjust dose according to response; children ≥6 years of age and adults: 50-75 mg orally once daily, adjust dose according to response

romiplostim: children ≥1 year of age and adults: 1-10 micrograms/kg subcutaneously once weekly, adjust dose according to response

avatrombopag: adults: 20-40 mg orally once daily, adjust dose according to response

without hematuria

Consider – antifibrinolytic

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Consider –

antifibrinolytic

Treatment recommended for SOME patients in selected patient group

Aminocaproic acid and tranexamic acid inhibit fibrinolysis and can help to stabilize clots that have already formed. These agents can be used as adjunctive treatment as they do not affect platelet count.

Aminocaproic acid and tranexamic acid are contraindicated in patients with hematuria because clots in the collecting system of the kidneys can lead to outlet obstruction.

Primary options

aminocaproic acid: children: 100 mg/kg intravenously as a loading dose initially, followed by 33.3 mg/kg/hour infusion, maximum 30 g/day; adults: 4-5 g intravenously as a loading dose initially, followed by 1 g/hour infusion, maximum 30 g/day

tranexamic acid: adults: 0.5 to 1 g orally three times daily

ACUTE

newly diagnosed child

asymptomatic or with minor bleeding symptoms

1st line – observation

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1st line –

observation

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 children, 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. Patients should have sufficient platelet levels before undergoing any type of procedure or surgery.[15]

Immune thrombocytopenia is a benign condition for most affected children, and major bleeding (even with prolonged, severe thrombocytopenia) appears to be rare.[22] Most manifestations are limited to the skin.

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]

with major bleeding symptoms

1st line – corticosteroid or IVIG or Rho(D) immune globulin

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1st line –

corticosteroid or IVIG or Rho(D) immune globulin

Treatment for children with newly diagnosed immune thrombocytopenia 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]

Intravenous immune globulin (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]

Patients develop mild, self-limited hemolysis on treatment with Rho(D) immune globulin, and there is a small risk of severe hemolysis and renal failure, but these are rare.[38][39] Immediate anaphylactic reactions and hypersensitivity reactions can also occur, and headaches are commonly reported. Steroid premedication may reduce side effects.[15]

Patients should have sufficient platelet levels before undergoing any type of procedure or surgery.[15]

Primary options

prednisone: 2-4 mg/kg/day orally given in 3-4 divided doses for 5-7 days, maximum 120 mg/day

methylprednisolone sodium succinate: 30 mg/kg intravenously every 24 hours for 3 days, followed by treatment with an oral corticosteroid as clinically indicated, maximum 1000 mg/dose

dexamethasone: 0.6 mg/kg orally once daily for 4 days, may repeat course, maximum 40 mg/day

Secondary options

immune globulin (human): 1 g/kg intravenously as a single dose, a second dose may be given if there is a poor response to initial treatment

Rho(D) immune globulin: consult specialist for guidance on dose

newly diagnosed adult (pregnant or nonpregnant):

platelet count ≥30 × 10³/microliter: asymptomatic without additional risk factors

1st line – observation

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1st line –

observation

Asymptomatic adults (or those with only minor mucocutaneous bleeding) with platelet count ≥30 × 10³/microliter who have no additional risk factors do not require immediate treatment; close observation is advised.

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.

Immune thrombocytopenia in adults is often a chronic disease. Spontaneous remission occurs in around 5% to 10% of cases.[40] Clinical follow-up and platelet count are required if bleeding symptoms develop or prior to surgery or dentistry.

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.

The criteria for starting treatment in pregnancy are the same as for nonpregnant patients.[20] Pregnant patients should be referred to a 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] A target platelet count of ≥50 × 10³/microliter is recommended for vaginal delivery or cesarean section. 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]

platelet count ≥30 × 10³/microliter: with bleeding symptoms and/or additional risk factors

1st line – corticosteroid and/or IVIG

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1st line –

corticosteroid and/or IVIG

Newly diagnosed adults with platelet count ≥30 × 10³/microliter who have bleeding symptoms (e.g., bruising, petechiae, purpura, oral mucosal bleeding, epistaxis) and/or additional risk factors can be treated first-line with a corticosteroid and/or intravenous immune globulin (IVIG).

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

For patients with a platelet count above >30 × 10³/microliter, the risks of morbidity from treatment should be carefully weighed against the potential benefits.[36]

Corticosteroids act against the immune-mediated destruction of platelets in immune thrombocytopenia, and they are typically the standard initial treatment. For nonpregnant patients, 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.

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.

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] In pregnant women, a target platelet count of ≥50 × 10³/microliter is recommended for vaginal delivery and cesarean section. 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]

Primary options

prednisone: 0.5 to 2 mg/kg/day orally for 1-3 weeks followed by a gradual taper, maximum 80 mg/day

methylprednisolone: 1000 mg intravenously every 24 hours for 3 days, followed by treatment with an oral corticosteroid as clinically indicated

dexamethasone: 40 mg orally once daily for 4 days, may repeat course

-- AND / OR --

immune globulin (human): 1 g/kg intravenously as a single dose, a second dose may be given if there is a poor response to initial treatment

1st line – Rho(D) immune globulin

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1st line –

Rho(D) immune globulin

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]

Rho(D) immune globulin may be safe to use in pregnancy, but evidence is lacking. In a small study involving Rh-positive and nonsplenectomized pregnant patients, Rho(D) immune globulin was shown to be 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.

Patients develop mild, self-limited hemolysis with Rho(D) immune globulin, and there is a small risk of severe hemolytic complications, but these are rare.[38][39] Immediate anaphylactic reactions also occur rarely; chills, fever and headaches are more common. Premedication with a corticosteroid may reduce side effects.[15]

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] In pregnant women, a target platelet count of ≥50 × 10³/microliter is recommended for vaginal delivery or cesarean section. 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]

Primary options

Rho(D) immune globulin: consult specialist for guidance on dose

platelet count <30 × 10³/microliter

1st line – corticosteroid and/or intravenous immunoglobulin (IVIG)

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1st line –

corticosteroid and/or intravenous immunoglobulin (IVIG)

Newly diagnosed adults with a platelet count <30 × 10³/microliter generally require treatment due to bleeding symptoms or increased risk of bleeding.[35]

A corticosteroid and/or intravenous immune globulin (IVIG) are considered first-line treatments.

Corticosteroids act against the immune-mediated destruction of platelets in immune thrombocytopenia, and they are typically the standard initial treatment.[88] For non-pregnant patients, 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. If a rapid increase in platelet count is required, IVIG can be given in combination with a corticosteroid.

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.[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.

Primary options

prednisone: 0.5 to 2 mg/kg/day orally for 1-3 weeks followed by a gradual taper, maximum 80 mg/day

methylprednisolone: 1000 mg intravenously every 24 hours for 3 days, followed by treatment with an oral corticosteroid as clinically indicated

dexamethasone: 40 mg orally once daily for 4 days, may repeat course

-- AND / OR --

immune globulin (human): 1 g/kg intravenously as a single dose, a second dose may be given if there is a poor response to initial treatment

1st line – Rho(D) immune globulin

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1st line –

Rho(D) immune globulin

Patients who are rhesus (Rh)-positive and nonsplenectomized may benefit from intravenous Rho(D) immune globulin, which has been shown to increase platelet count in more than 70% of cases (including both children and adults).[37] Intravenous Rho(D) immune globulin can be used first-line in these patients, but treatment response may be transient.[37]

Rho(D) immune globulin may be safe to use in pregnancy, but evidence is lacking. In a small study involving Rh-positive and nonsplenectomized pregnant patients, Rho D immune globulin was shown to be 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.

Patients develop mild, self-limited hemolysis on treatment with Rho(D) immune globulin, 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]

Patients should have sufficient platelet levels before undergoing any type of procedure or surgery. Guidelines provide recommendations for target platelet levelsfor dental procedures and surgery in adults (e.g., minor surgery ≥50 × 10³/microliter, major surgery ≥80 × 10³/microliter).[15] In pregnant women, a target platelet count of ≥50 × 10³/microliter is recommended for vaginal delivery or cesarean section. 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]

Primary options

Rho(D) immune globulin: consult specialist for guidance on dose

ONGOING

child: persistent or chronic disease

1st line – rituximab

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1st line –

rituximab

Immune thrombocytopenia (ITP; i.e., platelet count ≤100 × 10³/microliter) that does not resolve spontaneously or respond to first-line treatment is defined as persistent ITP if duration is 3-12 months after diagnosis and chronic ITP if duration is beyond 12 months after diagnosis.

Rituximab should be considered if there is treatment failure or intolerance with first-line treatments (e.g., corticosteroids, IVIG). 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] However, only 26% of patients (children and adults) treated with rituximab continue to have In a long-term follow-up study, only 26% of children with an initial response to rituximab treatment maintained a treatment-free response after 5 years.[76]

The treatment goal 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.

In cases of treatment failure or intolerance with rituximab, switching to another second-line drug (e.g., a thrombopoietin receptor agonists [eltrombopag or romiplostim]) may be considered.

Patients should have sufficient platelet levels before undergoing any type of procedure or surgery.[15]

Primary options

rituximab: 375 mg/square meter of body surface area intravenously once weekly for 4 doses

1st line – thrombopoietin receptor agonist

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1st line –

thrombopoietin receptor agonist

A thrombopoietin receptor agonist (eltrombopag or romiplostim) should be considered if there is treatment failure or intolerance with first-line treatments (e.g., corticosteroids, IVIG).

Eltrombopag and romiplostim are licensed for use in children >1 year of age with chronic ITP that is refractory to other treatments (e.g., corticosteroids, IVIG).

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) of 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]

In cases of treatment failure or intolerance with thrombopoietin receptor agonists, switching to another second-line drug (e.g., rituximab) may be considered.

Patients should have sufficient platelet levels before undergoing any type of procedure or surgery.[15]

Primary options

eltrombopag: children 1-5 years of age: 25-75 mg orally once daily, adjust dose according to response; children ≥6 years of age: 50-75 mg orally once daily, adjust dose according to response

romiplostim: children ≥1 year of age: 1-10 micrograms/kg subcutaneously once weekly, adjust dose according to response

2nd line – splenectomy (plus treatment to achieve target platelet level)

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2nd line –

splenectomy (plus treatment to achieve target platelet level)

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 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 Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria 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]

The goal of splenectomy is cure or long-lasting remission.

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

adult nonpregnant: persistent or chronic disease

1st line – thrombopoietin receptor agonist

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1st line –

thrombopoietin receptor agonist

Immune thrombocytopenia (ITP; i.e., platelet count ≤100 × 10³/microliter) that does not resolve spontaneously or respond to first-line treatment is defined as persistent ITP if duration is 3-12 months after diagnosis, and chronic ITP if duration is beyond 12 months after diagnosis.[1]

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

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] [ ] 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 not yet well developed.[52]

Differences in administration, dietary interactions, and side effects may affect the choice of thrombopoietin receptor agonist. Romiplostim is given once a week by subcutaneous injection. Eltrombopag and avatrombopag are once-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]

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 more than 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.

Primary options

romiplostim: 1-10 micrograms/kg subcutaneously once weekly, adjust dose according to response

eltrombopag: 50-75 mg orally once daily, adjust dose according to response

avatrombopag: 20-40 mg orally once daily, adjust dose according to response

1st line – rituximab

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1st line –

rituximab

Patients who do not respond to first-line treatment or relapse when corticosteroids are reduced or stopped may be offered rituximab as a second-line treatment option.

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 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 steroid premedication 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 for up to 6 months in patients previously treated with rituximab; ideally, vaccinations should be given >6 months before treatment with rituximab.[15][59]

Rituximab is used off-label for ITP.

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.

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

Primary options

rituximab: 375 mg/square meter of body surface area intravenously once weekly for 4 doses

1st line – fostamatinib

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1st line –

fostamatinib

Patients who do not respond to first-line treatment or relapse when corticosteroids are reduced or stopped may be offered fostamatinib as a second-line treatment option.

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 (i.e., platelet count ≥50 × 10³/microliter for 4 of 6 weeks) 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]

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.

Primary options

fostamatinib: 100-150 mg orally twice daily, adjust dose according to response

2nd line – splenectomy (plus treatment to achieve target platelet level)

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2nd line –

splenectomy (plus treatment to achieve target platelet level)

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.

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 immune thrombocytopenia) 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 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]

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.

3rd line – immunosuppressant or immunomodulatory drugs

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3rd line –

immunosuppressant or immunomodulatory drugs

In patients who fail treatment with multiple second-line drugs, salvage therapy with an immunosuppressant or immunomodulatory drug may be considered as off-label treatment for immune thrombocytopenia. 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 appears to be durable.[62][63][64]

Vinca alkaloids (e.g., vincristine) can be given in the acute setting only. Despite a high response rate (with a generally rapid response), use is limited by severe side-effects including peripheral neuropathy that may be irreversible.[15][65]

Primary options

azathioprine: 50-200 mg/day orally

cyclosporine modified: 3-6 mg/kg/day orally initially, adjust dose according to response, maximum 200 mg/day

cyclophosphamide: 50-200 mg/day orally

danazol: 200-800 mg/day orally

dapsone: 50-100mg/day orally

mycophenolate mofetil: 500-2000 mg/day orally

Secondary options

vincristine: consult specialist for guidance on dose

3rd line – low-dose corticosteroid or repeated IVIG infusions

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3rd line –

low-dose corticosteroid or repeated IVIG infusions

In patients who fail treatment with multiple second-line drugs, salvage therapy with a low-dose corticosteroid or repeated intravenous immune globulin (IVIG) infusions may be considered.

Low-dose corticosteroids 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 (optimally not more than 5 mg/day prednisone or equivalent).[15]

On-demand, repeated IVIG infusions 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.

Patients should have sufficient platelet levels before undergoing any type of procedure or surgery. Guidelines provide recommendations for target platelet levels.

Primary options

prednisone: consult specialist for guidance on dose; doses of ≤5 mg/day are recommended

immune globulin (human): 1 g/kg intravenously as a single dose

pregnant: persistent or chronic disease

1st line – high-dose methylprednisolone

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1st line –

high-dose methylprednisolone

Pregnant patients with immune thrombocytopenia that is unresponsive to initial prednisone or intravenous immune globulin (IVIG) should be treated with high-dose methylprednisolone, usually in combination with IVIG and/or azathioprine.[15][85]

Patients should have sufficient platelet levels before undergoing any type of procedure or surgery. Guidelines provide recommendations for target platelet levels.[15] In pregnant women, a target platelet count of ≥50 × 10³/microliter is recommended for vaginal delivery or cesarean section. 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]

Primary options

methylprednisolone sodium succinate: 1000 mg intravenously every 24 hours for 3 days, followed by treatment with an oral corticosteroid as clinically indicated

Consider – IVIG and/or azathioprine

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Consider –

IVIG and/or azathioprine

Treatment recommended for SOME patients in selected patient group

Patients usually receive intravenous immune globulin (IVIG) and/or azathioprine in addition to high-dose methylprednisolone.

Azathioprine has been safely used in pregnancy for other indications (e.g., systemic lupus erythematosus or renal transplantation).

Primary options

immune globulin (human): 1 g/kg intravenously as a single dose, a second dose may be given if there is a poor response to initial treatment

and/or

azathioprine: 50-200 mg/day orally

2nd line – rituximab

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2nd line –

rituximab

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 immune thrombocytopenia.

Primary options

rituximab: 375 mg/square meter of body surface area intravenously once weekly for 4 doses

2nd line – splenectomy

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2nd line –

splenectomy

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. Prelabour patients with ITP should have sufficient platelet levels. 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.

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Immune thrombocytopenia

Treatment algorithm

all patients (child or adult): with life- or organ-threatening bleeding

IVIG plus corticosteroid plus platelet transfusion

Primary options

thrombopoietin receptor agonist

Primary options

antifibrinolytic

Primary options

newly diagnosed child

observation

corticosteroid or IVIG or Rho(D) immune globulin

Primary options

Secondary options

newly diagnosed adult (pregnant or nonpregnant):

observation

corticosteroid and/or IVIG

Primary options

Rho(D) immune globulin

Primary options

corticosteroid and/or intravenous immunoglobulin (IVIG)

Primary options

Rho(D) immune globulin

Primary options

child: persistent or chronic disease

rituximab

Primary options

thrombopoietin receptor agonist

Primary options

splenectomy (plus treatment to achieve target platelet level)

adult nonpregnant: persistent or chronic disease

thrombopoietin receptor agonist

Primary options

rituximab

Primary options

fostamatinib

Primary options

splenectomy (plus treatment to achieve target platelet level)

immunosuppressant or immunomodulatory drugs

Primary options

Secondary options

low-dose corticosteroid or repeated IVIG infusions

Primary options

pregnant: persistent or chronic disease

high-dose methylprednisolone

Primary options

IVIG and/or azathioprine

Primary options

rituximab

Primary options

splenectomy