(See also Overview of Platelet Disorders.)
Immune thrombocytopenia usually results from development of an autoantibody directed against a structural platelet antigen. In childhood ITP, the autoantibody may be triggered by viral antigens. The trigger in adults is unknown, although in some countries (eg, Japan, Italy), ITP has been associated with Helicobacter pylori infection, and treatment of the infection has been followed by remission of the ITP. ITP tends to worsen during pregnancy and increases the risk of maternal morbidity.
Although often asymptomatic and identified only by a low platelet count on a routine assay, when present the symptoms and signs of immune thrombocytopenia are
Gross gastrointestinal (GI) bleeding and hematuria are less common. The spleen is of normal size unless it is enlarged by a coexisting viral infection or autoimmune hemolytic anemia (Evans syndrome). Like the other disorders of increased platelet destruction, ITP is also associated with an increased risk of thrombosis.
Immune thrombocytopenia is suspected in patients with isolated thrombocytopenia (ie, otherwise normal CBC and peripheral blood smear). Because manifestations of immune thrombocytopenia (ITP) are nonspecific, other reversible causes of isolated thrombocytopenia (eg, drugs, alcohol, lymphoproliferative disorders, other autoimmune diseases, viral infections) need to be excluded by clinical evaluation and appropriate testing. Typically, patients have coagulation studies, liver tests, and tests for infection with hepatitis C and HIV. Peripheral blood smear must be reviewed to help exclude other major causes of thrombocytopenia such as thrombotic thrombocytopenic purpura (TTP), inherited thrombocytopenia, and leukemia. Testing for antiplatelet antibodies may aid the diagnosis in some cases (1). The immature platelet fraction may be elevated in ITP when the platelet count is < 50,000/mcL.
Bone marrow examination is not required to make the diagnosis but is done if blood counts or blood smear reveals abnormalities in addition to thrombocytopenia, when clinical features are not typical, or if patients fail to respond to standard therapies (eg, corticosteroids). In patients with ITP, bone marrow examination reveals normal or possibly increased numbers of megakaryocytes in an otherwise normal bone marrow sample.
Al-Samkari H, Rosovsky RP, Karp Leaf RS: A modern reassessment of glycoprotein-specific direct platelet autoantibody testing in immune thrombocytopenia. Blood Adv 14;4(1):9–18, 2020. doi: 10.1182/bloodadvances.2019000868.
Children typically recover spontaneously, even from severe thrombocytopenia, in several weeks to months.
In adults, spontaneous remission occurs in 30% of patients in the first year, and up to 75% of patients improve within 5 years (1). However, many patients have mild and stable disease (ie, platelet counts > 30,000/mcL) with minimal or no bleeding; they are often discovered by the automated platelet counting now routinely done with complete blood count. Other patients have significant, symptomatic thrombocytopenia, although life-threatening bleeding and death are rare.
2019 guidelines are now available (1,2). Asymptomatic patients with a platelet count > 30,000/mcL and no bleeding do not require treatment and can monitored.
Adults with bleeding and a platelet count < 30,000/mcL are usually given an oral corticosteroid (eg, prednisone 1 mg/kg orally once/day) initially. An alternative, probably equally effective, corticosteroid regimen is dexamethasone 40 mg orally once/day for 4 days. In most patients, the platelet count increases within 2 to 5 days. However, in some patients, a response may take 2 to 4 weeks. When the corticosteroid is tapered after response, most adult patients relapse. Repeated corticosteroid treatments may be effective but increase the risk of adverse effects. Corticosteroids should not usually be continued beyond the first several months; other drugs may be tried in an attempt to avoid splenectomy.
Oral corticosteroids, IVIG, or IV anti-D immune globulin may also be given when a transient increase of the platelet count is required for tooth extractions, childbirth, surgery, or other invasive procedures. IVIG, or IV anti-D immune globulin are also useful for life-threatening bleeding in immune thrombocytopenia (ITP) but are rarely used for chronic treatment because their response may last for only a few days to weeks.
Splenectomy can achieve a complete remission in about two thirds of patients who relapse after initial corticosteroid therapy. Splenectomy is usually reserved for patients with severe thrombocytopenia (eg, < 15,000/mcL) in whom bleeding risk cannot be controlled with medical therapy or those whose disease persists after 12 months. If thrombocytopenia can be controlled with second-line medical therapies, splenectomy is often not necessary (1, 2). Splenectomy results in an increased risk of thrombosis and infection (particularly with encapsulated bacteria such as pneumococcus); patients require vaccination against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis (ideally > 2 weeks before the procedure).
Second-line medical therapies are available for patients with immune thrombocytopenia
Such patients usually have platelet counts < 10,000 to 20,000/mcL (and thus are at risk for bleeding). Second-line medical therapies include thrombopoietin receptor agonists, rituximab, fostamatinib, or other immunosuppressive drugs.
Thrombopoietin receptor agonists, such as romiplostim 1 to 10 mcg/kg subcutaneously once/week, eltrombopag 25 to 75 mg orally once/day and avatrombopag 20 mg/day have response rates > 85%. Thrombopoietin receptor agonists often need to be administered continuously to maintain the platelet count > 50,000/mcL, but emerging data suggest that one third of adults will undergo a treatment-free remission after 1 year and > 50% after 2 years.
Rituximab (375 mg/m2 IV once/week for 4 weeks) has a response rate of 57%, but only 21% of adult patients remain in remission after 5 years (3).
Fostamatinib, a spleen tyrosine kinase inhibitor, has a reported response rate of 18%. Dose is 100 mg orally twice/day, increasing to 150 mg twice/day after 1 month if the platelet count has not increased to > 50,000/mcL.
More intensive immunosuppression may be required with drugs such as cyclophosphamide, cyclosporine, mycophenolate, and azathioprine in patients unresponsive to other drugs who have severe, symptomatic thrombocytopenia.
In children or adults with immune thrombocytopenia and life-threatening bleeding, rapid phagocytic blockade is attempted by giving IVIG 1 g/kg once/day for 1 to 2 days or, in Rh-positive patients, a single dose of IV anti-D immune globulin 75 mcg/kg. IV anti-D immunoglobulin is only effective in patients who have not had a splenectomy and may be associated with severe complications such as severe hemolysis and disseminated intravascular coagulation. This treatment usually causes the platelet count to rise within 2 to 4 days, but the count remains high for only 2 to 4 weeks.
High-dose methylprednisolone (1 g IV once/day for 3 days) is easier to administer than IVIG or IV anti-D immune globulin but may not be as effective. Patients with ITP and life-threatening bleeding are also given platelet transfusions. Platelet transfusions are not used prophylactically.
Vincristine (1.4 mg/m2; maximum dose of 2 mg) has also been used in emergency situations but may produce neuropathy with repeated administration.
Treatment of children with immune thrombocytopenia is usually supportive because most children spontaneously recover. Even after months or years of thrombocytopenia, most children have spontaneous remissions. If mucosal bleeding occurs, corticosteroids or IVIG may be given. Corticosteroid and IVIG use is controversial because the increased platelet count may not improve clinical outcome. Splenectomy is rarely done in children. However, if thrombocytopenia is severe and symptomatic for > 6 months, then thrombopoietin receptor agonists (romiplostim, eltrombopag) should be considered.
Neunert C, Terrell DR, Arnold DM, et al: American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv 3(23):3829–3866, 2019. doi: 10.1182/bloodadvances.2019000966.
Provan D, Arnold DM, Bussel JB, et al: Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 3(22):3780–3817. doi: 10.1182/bloodadvances.2019000812.
Patel VL, Mahevas M, Lee SY, et al: Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood 119:5989–5995, 2012. doi: 10.1182/blood-2011-11-393975.
4. Bussel J, Arnold DM, Grossbard E, et al: Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo‐controlled trials. Am J Hematology 93: 921–930, 2018. doi: 10.1002/ajh.25125.
The immune system destroys platelets in the circulation and at the same time attacks bone marrow megakaryocytes, thereby reducing platelet production.
Other causes of isolated thrombocytopenia (eg, drugs, alcohol, lymphoproliferative disorders, other autoimmune diseases, viral infections) need to be excluded.
Children usually have spontaneous remission; in adults, spontaneous remission may occur during the first year but is less common (about 30%) than in children.
Corticosteroids (and sometimes IVIG or IV anti-D immune globulin) are first-line treatments for bleeding or severe thrombocytopenia.
Splenectomy is often effective but is reserved for patients in whom medical therapy is ineffective or those whose disease persists after 12 months.
Platelet transfusion is given only for life-threatening bleeding.