Immune Thrombocytopenic Purpura (ITP) Treatment & Management

Updated: Apr 23, 2018
  • Author: Craig M Kessler, MD, MACP; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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Treatment

Medical Care

The goal of medical care for immune thrombocytopenic purpura (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]

Although the paradigm may be shifting somewhat with the expanding experience with thrombopoietin receptor analogs in chronic ITP, the long-term consequences associated with their use remain to be established and the delayed platelet count responses these agents produce are not conducive to preventing or reversing the potential of acute bleeding complications in newly diagnosed ITP. Therefore, for the present, corticosteroids (ie, oral prednisone, intravenous [IV] methylprednisolone, or high-dose dexamethasone) [9, 10, 11] should remain the drugs of choice for the initial management of acute ITP. 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.

IV immunoglobulin (IVIG) has been the drug of second choice (after corticosteroids) for many years. [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.

Treatment in children

Most children with acute ITP do not require treatment, and thrombocytopenia resolves spontaneously. [7] The American Society of Hematology (ASH) recommends that children who have no bleeding or mild 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 symptoms. [49]

For pediatric patients requiring treatment, the ASH recommends a single dose of IVIg (0.8 to 1 g/kg) if a more rapid increase in the platelet count is desired, or a short course of corticosteroids, as first-line treatment. [8]

The ASH notes the significant risk of hemolysis with IV RhoD immune globulin (RhIG, anti-D immune ), and advises against its use in children with a hemoglobin concentration that is decreased because of bleeding, or in those with evidence of autoimmune hemolysis. However, the ASH suggests that a single dose of IV RhIG can be used as first-line treatment in Rh-positive, nonsplenectomized children with a negative direct antiglobulin test (DAT) who require treatment. [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, the ASH recommends considering rituximab or high-dose dexamethasone for second-line treatment. Rituximab or high-dose dexamethasone may also be considered as an alternative to splenectomy or as treatment for children and adolescents who do not respond favorably to splenectomy. [8]

Treatment in adults

In adults, treatment is recommended for a platelet count < 30×109/L. The ASH recommends that if treatment is needed and corticosteroids are given, longer courses (eg, prednisone 1 mg/kg orally for 21 days then tapered) are preferred over shorter courses of corticosteroids or IVIG as first-line treatment. IVIG be used with corticosteroids in patients who require a more rapid increase in platelet count. If corticosteroids are contraindicated, either IVIG (initially, 1 g/kg in a single dose) or IV RhIG (in appropriate patients) may be used as a first-line treatment. [8]

The ASH suggests consideration of thrombopoietin receptor agonists for patients at risk of bleeding when splenectomy is contraindicated and at least one other therapy has failed, and recommends thrombopoietin receptor agonists In adult patients  who relapse after splenectomy and are at risk for bleeding. The ASH suggests consideration of rituximab in patients at risk of bleeding when one line of therapy (eg, corticosteroids, IVIg, splenectomy) has failed. [8]

Gudbrandsdottir et al reported that, compared with dexamethasone monotherapy, treatment with the combination of dexamethasone and rituximab resulted in higher response rates (58%, versus 37% with dexamethasone alone; P = 0.02), 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. [50]

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 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 (>50 × 103/µL) typically have minimal purpura, and the risk of a severe hemorrhage is low. They may be treated without a specific medication.

  • Platelet transfusions may be required to control clinically significant bleeding but are not recommended for prophylaxis. Transfused platelets also have decreased circulation, and repeated platelet transfusions may lead to platelet alloimmunization.

Fostamatinib was approved by the FDA in April 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 3 trials and an open-label extension trial. Results from the randomized trials showed more patients experienced a platelet response with fostamatinib compared 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%). [94]

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 1mg/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.

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, dapsonevinblastine, vincristine, ascorbic acid, colchicine, and interferon alfa. [51, 52, 53, 54, 55, 56, 57]

In 2008, two thrombopoietin receptor agonists, romiplostin (Nplate) and eltrombopag (Promacta), became available for patients with chronic ITP. In August 2015, the U.S. Food and Drug Administration 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. [58]

The limited clinical experiences with these agents are promising. However, the ultimate efficacy and safety of these new agents will not be fully evaluable until data on larger numbers of patients become available.

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. [59] 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. [60]

In a phase 3 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, odds ratio 9.1). However, further studies are needed to determine long-term efficacy, safety, and remission rates. [61]  

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. [62]

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. [63]

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%). [63]

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Surgical Care

In persons with acute immune thrombocytopenic purpura (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. [64]

Laparoscopic splenectomy is an interventional approach that is less invasive than traditional splenectomy and offers the promise of decreased postoperative morbidity and shorter recovery. [65, 66, 67] 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 [68, 69, 70] and Babesia, as follows [71] :

  • 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, [72] a twofold increase in deaths from cardiovascular disease, [73] and an increased rate of pulmonary hypertension [74] .

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. [75]

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. [76, 77]

  • 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.

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Consultations

Selecting a treatment program for immune thrombocytopenic purpura (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. [78, 79]

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.

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