Sections

Treatment

Approach Considerations

The goal of medical care for immune thrombocytopenia (ITP) is to increase the platelet count to a safe level, permitting patients to live normal lives while awaiting spontaneous or treatment-induced remission. ITP has no cure, and relapses may occur years after seemingly successful medical or surgical management.^[6]

The treatment paradigm is shifting, with expanding experience with earlier use of thrombopoietin receptor analogs (TPO-RA; TPO-mimetics) in chronic ITP. However, this is not yet the standard of care. These agents may not be conducive to preventing or reversing the potential for acute bleeding complications in newly diagnosed ITP, given the delayed platelet count responses they produce. However, data are maturing on their use and long-term effectiveness.

Corticosteroids (ie, oral prednisone or high-dose dexamethasone)^{[9, 10, 11]}remain the drugs of choice for the initial management of acute ITP, especially in the setting of life-threatening thrombocytopenia or when response in the platelet count is needed in an urgent or emergent setting. Treatment with corticosteroids may not only reduce the rate of platelet destruction but may also rapidly alter endothelial cell integrity to facilitate primary hemostasis and to reduce bleeding and bruising.

Because corticosteroid administration may change marrow morphology, performance of a bone marrow aspiration and biopsy should be considered to confirm the diagnosis of ITP if the clinical presentation, patient age, or other findings are atypical for acute ITP before the patient is treated with corticosteroids.

TPO-RA and rituximab are second-line options for patients with ITP lasting 3 months or more and in those who are corticosteroid dependent or have no response to corticosteroids. For adults who have had ITP for longer than 12 months, splenectomy is also a second-line option. In studies from Asia—principally, China—cyclosporine has demonstrated efficacy and safety as second-line treatment for ITP in adults and children, typically as part of combination therapy.^[58]

Intravenous immunoglobulin (IVIG) can be the drug of second choice (after corticosteroids) for some patients, such as when a rapid increase in platelet count is important.^{[12, 13]}However, for Rh(D)-positive patients with ITP and intact spleens, IV Rho immunoglobulin (RhIG) offers comparable efficacy, less toxicity, greater ease of administration, and a lower cost than IVIG.^{[14, 15]}

The limitation of using IV RhIG is the lack of efficacy in Rh(D)-negative or splenectomized patients. Also, IV RhIG may induce immune hemolysis (immune hemolytic anemia) in Rh(D)-positive persons, which is the most common adverse effect, and should not be used when the hemoglobin concentration is less than 8 g/dL. Sporadic cases of massive intravascular hemolysis^[16]disseminated intravascular coagulation (particularly in elderly individuals), and renal failure^[17]have been reported.

The treatment of chronic, refractory ITP may introduce risks of toxicity from medications that are comparable in severity to the risks of untreated thrombocytopenia. These treatments also may impact adversely on the patient's quality of life.^[59]

Splenectomy is an option for chronic ITP, as it is associated with long-term treatment-free remissions, but it is very rarely indicated in pediatric patients. Because of the significant rate of spontaneous remission or stabilization in ITP, guidelines recommend deferring splenectomy for at least 12 months from diagnosis.^{[8, 46]}Very rarely, splenectomy may be performed as an emergency measure.

Thrombopoietin Receptor Agonists

For many years, the only treatment options after corticosteroids, IV RhIG, IVIG, and rituximab were cyclophosphamide, azathioprine, and danazol. Interventions with decreased certain efficacy and with conflicting reports in the literature include alemtuzumab, azathioprine, danazol, dapsone, vinblastine, vincristine, ascorbic acid, colchicine, and interferon alfa.^{[60, 61, 62, 63, 64, 65, 66]}

In the past decade, thrombopoietin receptor agonists (TPO-RAs) have entered clinical practice as second-line agents, with robust evidence supporting their efficacy.^[46]Three TPO-RAs are currently available: romiplostin (Nplate), eltrombopag (Promacta), and avatrombopag (Doptelet). In cases of inefficacy or intolerance of one TPO-RA, switching to another TPO-RA may prove useful.^[46]

Romiplostin

The TPO receptor agonist romiplostim became available for patients with chronic ITP in 2008. Romiplostinm is administered weekly via subcutaneous injection and increases platelet counts within 5 to 8 days, with levels returning to baseline after 28 days.

In one prospective, randomized controlled study comparing romiplostin with the standard of care for the treatment of chronic ITP, romiplostim administration was associated with higher rates of platelet count responses, decreased need for splenectomy, fewer episodes of serious bleeding and blood transfusions, and decreased need for initiating additional medical treatments. Romiplostim therapy was also associated with improved quality of life.^[67]In a study of long-term romiplostim treatment, a small cohort of children with severe chronic ITP increased and maintained platelet counts for over 4 years, with good tolerability and without significant toxicity.^[68]

In a phase III double-blind study of 62 symptomatic children with persistent or chronic ITP who were randomly assigned to receive weekly romiplostim or placebo for 24 weeks, durable platelet response was seen in 52% of patients receiving romiplostim vs.10% of those in the placebo group (p=0.002,906582 odds ratio 9.1). However, further studies are needed to determine long-term efficacy, safety, and remission rates.^[69]

A systematic review concluded that romiplostim is effective and generally well tolerated in patients 65 years of age and older with ITP. Complications included nonsignificant trends toward increased risks of grade ≥3 bleeding and thromboembolic events.^[70]

Caveats for the use of romiplostim, and other TPO-mimetics, are as follows:

Abrupt discontinuation of these agents, or non-adherence to their therapeutic regimens, can result in a rapid nadir in platelet counts, often to levels that may predispose to catastrophic bleeds.
A variable percentage (around 30%) of patients who have achieved complete remission with TPO-mimetic therapy may maintain a durable remission after tapering of the TPO-mimetic. There are no biomarkers or specific patient characteristics that can identify patients who are likely to achieve durable remissions; use in pregnancy is not recommended but anecdotally appears to be safe.
Arterial and venous thrombotic events have been reported during TPO-mimetic use, but other than perhaps portal vein thrombosis, such events do not occur any more frequently than in those ITP patients receiving standard non–TPO-mimetic therapy. ^[71]

Eltrombopag

Like romiplostim, eltrombopag also became available in 2008. In 2015, the US Food and Drug Administration (FDA) expanded the indication for eltrombopag to include treatment of chronic ITP in patients 1 year of age and older who have not achieved an appropriate response with other medical therapy or splenectomy.^[72] An oral TPO receptor agonist, eltrombopag increases platelet counts after 8 days of daily dosing.

Eltrombopag was studied in a phase III double-blind trial in adults with previously treated ITP lasting more than 6 months and with platelet counts lower than 30,000/µL. Patients received treatment with local standard care plus eltrombopag (50 mg) or placebo for 6 months. Of 196 patients in the study, 106 (79%) patients in the eltrombopag group responded to treatment at least once, compared with 17 (28%) in the placebo group. Toxic reactions in the eltrombopag group included thromboembolic events (2%), mild increases in alanine aminotransferase levels (3%), and increased total bilirubin levels (4%).^[73]

Eltrombopag has a boxed warning for the risk of severe and potentially life‐threatening hepatotoxicity. Dose reductions are needed for patients with hepatic impairment and some patients of East Asian ancestry. Eltrombopag must be taken on an empty stomach (1 hr before or 2 hrs after meals).

Avatrombopag

Avatrombopag, an oral TPO receptor agonist, was approved by the FDA in 2019 for adults with chronic ITP who have had an insufficient response to a previous treatment. Results from a phase III randomized trial that supported the approval showed avatrombopag administration resulted in a platelet count of at least 50,000/µL at day eight of therapy in the majority of patients, with efficacy superior to placebo in maintaining platelet counts in the target range during the 6-month treatment period.^[74]

Unlike romiplostim, which must be taken on an empty stomach, avatrombopag can be taken with food; unlike eltrombopag, it has not been associated with hepatotoxicity. In retrospective study of 44 adult patients with chronic ITP switched to avatrombopag after inadequate response to eltrombopag or romiplostim, 41 patients (93%) achieved a platelet response (≥50 × 10⁹/L) and 38 patients (86%) achieved a complete response (≥100 × 10⁹/L).^[75]

Treatment in Children

Most children with acute ITP do not require treatment, and thrombocytopenia resolves spontaneously.^[7]American Society of Hematology (ASH) guidelines recommend that children who have no bleeding or minor bleeding (eg, cutaneous manifestations such as bruising and petechiae) be managed with observation alone regardless of platelet count.^[8]A retrospective review by Schultz et al found that this approach did not lead to an increase in later treatment or an increase in delayed bleeding.^[76]

For pediatric patients requiring treatment, ASH suggests a short course of corticosteroids for first-line treatment rather than IVIG or anti-D immunoglobulin.^[8]

For initial (induction) treatment, in patients with a platelet count of 20-30 × 10⁹/L [20-30,000/µL] and/or mucocutaneous bleeding), one regimen is prednisone 4-8 mg/kg/d with the intent of a rapid and complete taper after 7-10 days or when the platelet count reaches 50 × 10⁹/L (50,000/µL), whichever occurs first. In critical situations, an IV infusion of a corticosteroid may be preferable (eg, methylprednisolone 30 mg/kg IV, up to 1 g; or dexamethasone, 28 mg/m².^[46]

Immunoglobulin regimens are RhIG, 75/µg/kg IV (off-label dose) for the Rh-positive patient or IVIG 1.0 g/kg for the Rh-negative patient. If the patient has clinically significant purpura or bleeding at presentation, consider infusing the first dose of IV RhIG or IVIG at the time of initial therapy with corticosteroids.

Repeat the infusions at 3- to 4-week intervals (maintenance) until a satisfactory platelet count is achieved. If the platelet count is not maintained after 3-4 infusions, the case might be refractory, and a different treatment should be considered. Conditions refractory to IV RhIG may respond to IVIG, and vice versa. If the patient's hemoglobulin level decreases to 8.0 g/dL during treatment with IV RhIG, temporarily switch to IVIG until the level recovers. In this situation, the patient's condition should not be considered refractory to IV RhIG.

The ASH guidelines acknowledge the risk of hemolysis with IV Rh_oD immune globulin (RhIG, anti-D immune) and the black box warning related to fatal intravascular hemolysis, but notes these are rare events.^[8] An advantage of IV RhIG is that if bone marrow aspiration is unacceptable to parents and if the diagnosis of acute ITP is equivocal, IV RhIG is an effective treatment that avoids the problem of a misdiagnosis of acute leukemia because of steroid-related changes in the marrow.

For children or adolescents with ITP who have significant ongoing bleeding despite treatment with IVIG, RhIG, or conventional doses of corticosteroids, ASH suggests a TPO-RA rather than rituximab or splenectomy as second-line treatment. Of the TPO-RAs, eltrombopag and romiplostim are approved for use in children age 1 year and older.

Rituximab is not approved for use in ITP. Nevertheless, rituximab at a standard dose of 375 mg/m² per week for 4 weeks appears to be safe and effective in pediatric patients with ITP, with overall response rates of 23% to 69%.^{[8, 46, 77, 78, 79]}

Treatment in Adults

In adults, treatment is recommended for a platelet count < 30×10⁹/L. The ASH recommends that if treatment is needed, shorter courses of corticosteroids (≤6 weeks) are preferred over prolonged courses (> 6 weeks including treatment and taper) as first-line treatment. The guidelines suggest either prednisone (0.5-2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days) as the type of corticosteroid for initial therapy. ^[8]

In adults with ITP lasting ≥3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guidelines suggest either splenectomy or a TPO-RA. In adults who are going to be treated with aTPO-RA, either eltrombopag or romiplostim is suggested by the ASH guidelines. ASH also suggests rituximab over splenectomy.^[8]

Gudbrandsdottir et al reported that treatment with the combination of dexamethasone and rituximab resulted in higher response rates than with dexamethasone monotherapy (58%, versus 37% with dexamethasone alone; P = 0.02), as well as longer time to relapse (P = 0.03) and longer time to rescue treatment (P = 0.007). However, the incidence of grade 3 to 4 adverse events was higher in the rituximab plus dexamethasone group (P = 0.04). The study included 113 adult patients with newly diagnosed, symptomatic primary ITP.^[80]

Additional precautions are required for patients with hypertension, peptic ulcers, recent aspirin ingestion, or other risk factors for increased bleeding. Considerations are as follows:

Aspirin inhibits platelet function by acetylating platelet cyclooxygenase, increasing the risk of bleeding because it adds a prolonged platelet functional defect to the quantitative defect already present from the severe thrombocytopenia. In addition, platelet dysfunction may be induced by the platelet antibody, which is potentiated by the superimposition of the aspirin-platelet defect. Because of this effect, aspirin is contraindicated in persons with ITP.
Adults whose platelet counts are greater than 50× 10⁹/L typically have minimal purpura, and the risk of a severe or life-threatening hemorrhage is low. They may be treated without a specific medication.
Platelet transfusions may be required to control clinically significant or catastrophic bleeding but are not recommended for prophylaxis. Transfused platelets have decreased circulation time, and repeated platelet transfusions may lead to platelet alloimmunization.

Fostamatinib

Fostamatinib (Tavalisse) was approved by the US Food and Drug Administration (FDA) in 2018 for thrombocytopenia in adults with chronic ITP who have had an insufficient response to a previous treatment. It is the first spleen tyrosine kinase (SYK) inhibitor approved in the US. Approval was based on the FIT clinical program (n=163), which included 2 randomized placebo-controlled phase III trials and an open-label extension trial.^[81]

In those randomized trials, more patients experienced a platelet response with fostamatinib than with placebo (18% vs 0% and 16% vs 4%). In the open-label expansion trial, 23% of patients who had received placebo in the previous randomized trials experienced a platelet response. Fewer bleeding episodes were observed in patients in the fostamatinib arm compared with placebo (29% vs 37%). Most of the patients who responded demonstrated durable platelet increments.^[81]

Refractory disease

Adults whose disease is not controlled with a prednisone-induced increase in platelet count that is maintained by IV RhIG or IVIG and whose conditions do not respond to four weekly infusions of rituximab are candidates for splenectomy. After these serial experiences, such patients are likely to have had thrombocytopenia for at least 6 months and, therefore, are categorized as having chronic ITP.

Eltrombopag, romiplostim, and avatrombopag offer potential maintenance of safe levels of platelet counts for adults who qualify by having ITP for at least 6 months and whose conditions are refractory to conventional medical management (prednisone, IV RhIG, IVIG, rituximab), and whose platelet count is not maintained in a satisfactory range after splenectomy.^[82]

Treatment in Pregnant Women

Pregnant women with no bleeding manifestations whose platelet counts are 30 × 10⁹/L or higher do not require any treatment until 36 weeks' gestation, unless delivery is imminent. For pregnant women with platelet counts below 30 × 10⁹/L, or clinically relevant bleeding, first-line therapy is oral corticosteroids or IVIG. Oral prednisone and prednisolone cross the placenta less readily than dexamethasone. Although ASH guidelines recommend a starting dose of prednisone of 1 mg/kg daily, other experts recommend a starting dose of 0.25 to 0.5 mg/kg, as there is no evidence that a higher starting dose is better. The recommended starting dose of IVIG is 1 g/kg.^[18]

Refractory ITP in pregnancy can be treated with corticosteroids and IVIG in combination, or splenectomy (in the second trimester).^[18]Rarely, splenectomy may be required to manage acute hemorrhage.^[19]

Azathioprine and RhIG are relatively contraindicated in pregnancy. The standard dose of IV RhIG for ITP contains approximately 10-fold the concentration of anti-D that is in the standard antepartum dose of intramuscular RhIG for Rh immunoprophylaxis. Other third-line agents that are not recommended in pregnancy, but whose use in this setting has been described, include the following agents (all of them pregnancy category C)^[18]:

Cyclosporine
Dapsone
Thrombopoietin receptor agonists
Alemtuzumab
Rituximab

For more information, see Immune Thrombocytopenia and Pregnancy.

Surgical Care

In persons with acute immune thrombocytopenia (ITP), splenectomy usually results in rapid, complete, and life-long clinical remission. In persons with chronic ITP, the results of splenectomy are typically less predictable than they are in patients with acute ITP. Platelet counts may not fully revert to normal values, and relapses are not uncommon after 5 years. Studies suggest that the initiation of thrombopoietin mimetics may obviate splenectomy in a significant number of adults with chronic ITP.^[83]

Laparoscopic splenectomy is an interventional approach that is less invasive than traditional splenectomy and offers the promise of decreased postoperative morbidity and shorter recovery.^{[84, 85, 86]}However, the ultimate role for laparoscopic splenectomy in ITP depends on long-term follow-up to determine whether this approach is as effective as conventional splenectomy for visual scrutiny of the abdominal cavity to identify accessory spleens.

Splenectomy results in a lifelong increased risk of sepsis from infection by encapsulated bacteria^{[87, 88, 89]}and Babesia, as follows^[90]:

In adults, this risk is estimated to be approximately 1%, with a fatal outcome in approximately 1 per 1500 patient-years.
In children, the risk of bacterial sepsis after splenectomy is estimated to be 1-2%. Many pediatricians recommend delaying splenectomy until children are 5 years of age.
These estimates are presumably based on early data and may be inflated, given the increased alertness to the importance of early treatment, availability of more effective antibiotics, and availability of vaccines against specific encapsulated bacteria.
Before one concludes that medical management and splenectomy have failed and that treatment with alternative options is needed, perform an imaging study to ensure that the problem is not associated with an accessory spleen.

In addition, splenectomy has been associated in adults with an increased incidence of venous and arterial thrombosis,^[91]a twofold increase in deaths from cardiovascular disease,^[92]and an increased rate of pulmonary hypertension^[93].

If elective splenectomy is planned for a child or an adult, initiate immunization with Haemophilus influenzae type b vaccine at least 14 days before surgery.^[94]

Immunize adults and children older than 2 years with polyvalent Streptococcus pneumoniae vaccine and quadrivalent meningococcal polysaccharide vaccine.

Evaluate patients who have a relapse after having an initially satisfactory response to splenectomy for the possible presence of an accessory spleen.^{[95, 96]}

An accessory spleen is strongly suggested if Howell-Jolly bodies appeared on the peripheral smear after splenectomy but are no longer present. However, the continued presence of Howell-Jolly bodies does not exclude an accessory spleen.
Imaging techniques using radionucleotide-labeled sulfur colloid, heat-damaged RBCs, or, preferably, autologous platelets provide more useful information than standard imaging with CT scanning or MRI.

Consultations

Selecting a treatment program for immune thrombocytopenia (ITP) requires knowledge of current options and consultation with a hematologist.

If 6 months of medical management fails to increase the platelet count to a safe range (about 30,000/µL), splenectomy becomes an option. Early consultation with a surgeon is useful for planning management.^{[97, 98]}

If the platelet count is less than 10 × 10⁹/L (< 10 × 10³/µL) or if the patient has other evidence of a clinically significant risk of serious hemorrhage, consult a radiologist to determine what noninterventional imaging procedures are available in case of emergency.

Guidelines

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Media Gallery

Peripheral blood smear from a patient with immune thrombocytopenia (ITP) shows a decreased number of platelets, a normal-appearing neutrophil, and normal-appearing erythrocytes. ITP is diagnosed by excluding other diseases; therefore, the absence of other findings from the peripheral smear is at least as important as the observed findings. This smear demonstrates the absence of immature leukocytes (as in leukemia) and fragmented erythrocytes (as in thrombotic thrombocytopenic purpura) and no clumps of platelets (as in pseudothrombocytopenia).

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Table 1. Bleeding scale for pediatric patients with ITP

Table 1. Bleeding scale for pediatric patients with ITP

Grade	Bleeding	Management approach
Grade 1 (minor)	Minor bleeding, few petechiae (≤100 total) and/or ≤5 small bruises (≤3 cm in diameter), no mucosal bleeding	Consent for observation
Grade 2 (mild)	Mild bleeding, many petechiae (>100 total) and/or >5 large bruises (>3 cm in diameter), no mucosal bleeding	Consent for observation
Grade 3 (moderate)	Moderate bleeding, overt mucosal bleeding, troublesome lifestyle	Intervention to reach grade 1 or 2
Grade 4 (severe)	Severe bleeding, mucosal bleeding leading to decrease in Hb > 2 g/dL or suspected internal hemorrhage	Intervention

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Author

Craig M Kessler, MD, MACP Professor, Department of Medicine and Pathology, Division of Hematology/Oncology, Georgetown University School of Medicine; Director, Clinical Coagulation Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Hospital

Disclosure: Received honoraria from NovoNordisk for consulting; Received grant/research funds from NovoNordisk for other; Received honoraria from Baxter-Immuno for consulting; Received honoraria from Octapharma for speaking and teaching; Received grant/research funds from Octapharma for none; Received consulting fee from Amgen for consulting; Received honoraria from Bayer for review panel membership.

Coauthor(s)

Hira Latif, MD Assistant Professor, Division of Hematology/Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center

Hira Latif, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, International Society on Thrombosis and Haemostasis, Pakistan Medical and Dental Council

Disclosure: Nothing to disclose.

Julia M Cunningham, MD Assistant Professor of Medicine, Division of Hematology and Oncology, Attending Physician in Hematology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center

Julia M Cunningham, MD is a member of the following medical societies: American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Hemostasis and Thrombosis Research Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine

Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion; Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel.

Additional Contributors

S Gerald Sandler, MD, FCAP, FACP Professor Emeritus of Medicine and Pathology, Georgetown University School of Medicine

S Gerald Sandler, MD, FCAP, FACP is a member of the following medical societies: American Association of Blood Banks, College of American Pathologists, International Society of Blood Transfusion

Disclosure: Nothing to disclose.