Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966. Erratum in: Blood Adv. 2020 Jan 28;4(2):252. PMID: 31794604; PMCID: PMC6963252.
Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019 Nov 26;3(22):3780-3817. doi: 10.1182/bloodadvances.2019000812. PMID: 31770441; PMCID: PMC6880896.
Definition and EtiologyTop
Immune thrombocytopenia (ITP), formerly termed idiopathic thrombocytopenic purpura, is an acquired immune disease characterized by isolated thrombocytopenia, defined as platelet counts <100×109/L, with no known causes. For primary ITP, the etiology is unknown. Secondary ITP can be caused by certain infections, underlying autoimmune diseases, lymphoproliferative diseases, or drugs.
Clinical Features and Natural HistoryTop
ITP is classified on the basis of its duration as newly diagnosed (<3 months), persistent (3-12 months), or chronic (≥12 months). In adults the disease is usually chronic and often asymptomatic, and it is associated with remissions and relapses. In 10% to 20% of adult patients ITP resolves spontaneously. Typical manifestations of ITP include skin petechiae or bruises, epistaxis, gingival bleeding, oral mucous membrane blood blisters, heavy and prolonged menstrual bleeding, or, rarely, intracranial hemorrhage. In some patients the only features are cutaneous petechiae and bruising. Petechiae are usually located on the mucous membranes and the skin of distal dependent extremities (eg, feet or ankles) or underneath tight clothing. Tissue injury causes excessive bleeding, but gastrointestinal and intracranial hemorrhages are rare.
1. Complete blood count (CBC): Isolated thrombocytopenia, increased mean platelet volume (MPV), increased numbers of young platelets.
2. Blood film is required to exclude platelet clumping (pseudothrombocytopenia) or other thrombocytopenic disorders associated with abnormalities of red blood cells (eg, schistocytes in thrombotic thrombocytopenic purpura) or of white blood cells (eg, immature forms or blasts in leukemia).
3. Bone marrow aspiration or biopsy might be considered in patients aged >60 years and in patients who do not respond to typical ITP treatments (glucocorticoids or IV immunoglobulin [IVIG]) to exclude myelodysplastic syndrome or other bone marrow disorders. Bone marrow examination is not necessary in patients with typical ITP.
4. Other studies: Tests for HIV and hepatitis C virus should be done. Helicobacter pylori testing should be considered in patients from certain countries (Japan, Italy); antinuclear antibodies should be considered when systemic lupus erythematosus is suspected; pregnancy test. Platelet autoantibody testing has low sensitivity and requires using specialized test methods; thus, it has not been adopted into routine practice.
Isolated thrombocytopenia (platelet count <100×109/L) with an otherwise normal CBC in a patient in whom other causes have been excluded, based on the investigations listed above. Clues to the diagnosis of ITP are thrombocytopenia (platelet count often <20×109/L), platelet count response after glucocorticoids or IVIG, and, for secondary ITP, improvement in platelet counts after treatment of the underlying cause (eg, HIV, H pylori).
Other causes of thrombocytopenia: see Platelet Disorders: General Considerations.
Treatment is not necessary in patients who are not bleeding. Treatment might be considered in adult patients with extreme thrombocytopenia (eg, <30×109/L) or prior to a procedure. Most children who do not have bleeding symptoms can be carefully monitored without treatment, since many children improve spontaneously.
1. Glucocorticoids: Cycles of dexamethasone 40 mg/d for 4 days every 14 or 28 days (1-4 cycles) or alternatively oral prednisone 1 to 1.5 (usually 1) mg/kg/d for 1 to 2 weeks, followed by a taper (for ~6-8 weeks in total). Prolonged exposure to glucocorticoids should be avoided because of adverse effects. For patients treated with glucocorticoids for >3 months, prevention of osteoporosis is necessary (see Osteoporosis). In patients not responding to prednisone, the drug should be discontinued within 1 week.
2. IVIG can be used as a first-line therapy in patients with or at risk for life-threatening hemorrhage, those who are unable to tolerate glucocorticoids, those requiring immediate surgery, or pregnant patients who require urgent treatment.
3. Patients with H pylori infection should be considered for H pylori eradication therapy, as this can rarely lead to an improvement in the platelet counts (see Peptic Ulcer Disease).
4. Rhesus immunoglobulin (RhIG), also referred to as anti-D immunoglobulin (anti-D Ig): RhIG can be used for ITP patients whose blood group is rhesus positive (D+). Because this treatment can cause hemolysis and, rarely, disseminated intravascular coagulation, it has fallen out of favor in recent years. It is ineffective in patients who have had a splenectomy and is more commonly used in children.
The choice of second-line treatments depends on patient factors and patient values and preferences. For example, rituximab may be preferred for younger females within the first year of the ITP diagnosis, and splenectomy may be preferred for patients who prioritize a durable platelet count response without the use of maintenance pharmacologic treatments.
1. Splenectomy: Indications for splenectomy are considered on a case-by-case basis in patients with ITP who are refractory to first-line therapy. Before splenectomy a trial of second-line pharmacotherapy may be used (see below). Splenectomy should generally be delayed until ≥12 months from the diagnosis, since spontaneous remissions can occur. The most common complications of splenectomy include infections and venous thrombosis. Splenectomy leads to remission in up to 70% of patients. In the remaining patients continued pharmacologic treatments at the lowest possible dose may be necessary. Ideally, the platelet count should be >50×109/L prior to splenectomy; however, many splenectomies have been done at lower platelet count levels without bleeding complications, since the platelet count often increases immediately postoperatively. At least 2 weeks before splenectomy (and if this is not feasible, as soon as possible after splenectomy), the patient should receive vaccines against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae (see Immunization and Selected Vaccinations in Adults). Some vaccinations should be repeated every 5 years, as per vaccination guidelines.
2. Rituximab is widely used as a second-line agent in patients with ITP. It is associated with a platelet count response in ~50% to 60% of patients; however, the response typically does not last >12 to 18 months. Approximately 20% of patients have a durable remission that lasts >5 years. Rituximab may be most effective in young women with a recent diagnosis of ITP (within the first 12 months) and in patients with an underlying autoimmune disease.
3. Thrombopoietin-receptor agonists: Romiplostim, eltrombopag. Thrombopoietin-receptor agonists are associated with a platelet count response in ~80% of patients. Romiplostim is administered as a weekly subcutaneous injection. Eltrombopag is a daily oral pill. Both drugs have been associated with a slightly increased risk of thrombosis. Eltrombopag can be associated with liver toxicity in ~15% of patients. Avatrombopag is another thrombopoietin-receptor agonist that has been approved in the United States for the ITP indication.
4. Fostamatinib is an oral spleen tyrosine kinase (Syk) inhibitor that has recently been approved in North America for the treatment of chronic ITP.
5. Other drugs can be used as maintenance therapy for ITP in the second line, including immunosuppressive agents, such as mycophenolate mofetil, azathioprine, or cyclosporine (INN ciclosporin). Danazol and dapsone have also been used.
For patients with severe hemorrhagic complications, IVIG (1 g/kg/d for 1-2 days) and glucocorticoids (IV methylprednisolone 1 g/d) should be used in combination. For patients with life-threatening bleeding, platelet transfusions should be added.
For patients who require surgery, IVIG or thrombopoietin-receptor agonists are good treatment options; however, IVIG has a faster onset of action (12-24 h) and thus may be preferable when the surgery is urgent. Glucocorticoids can also be used, but they may be associated with delayed wound healing.
Oral prednisone or IVIG are safe in pregnancy. Vaginal delivery is recommended for patients with ITP unless there is an obstetrical indication for cesarean delivery. In general, for vaginal deliveries, platelet counts should be ≥30×109/L; for cesarean delivery, platelet counts should be ≥50×109/L; and for epidural analgesia, platelet counts should be ≥80×109/L, although supporting evidence for these thresholds is lacking.