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Immune Thrombocytopenia in Adults: Modern Approaches to Diagnosis and Treatment

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Immune Thrombocytopenia in Adults: Modern Approaches to Diagnosis and Treatment Published online: 2019-12-12 275 Immune Thrombocytopenia in Adults: Modern Approaches to Diagnosis and Treatment Hanny Al-Samkari, MD1 David J. Kuter, MD, DPhil1 1 Division of Hematology, Massachusetts General Hospital, Harvard Address for correspondence Hanny Al-Samkari, MD, Division of Medical School, Boston, Massachusetts Hematology, Massachusetts General Hospital, Suite 118, Room 112, Zero Emerson Place, Boston, MA 02114 Semin Thromb Hemost 2020;46:275–288. (e-mail: [email protected]). Abstract Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20,000 people. Patients typically present with clinically benign mucocutaneous bleeding, but morbid internal bleeding can occur. Diagnosis remains clinical, possible only after ruling out other causes of thrombocytopenia through history and laboratory testing. Many adult patients do not require treatment. For those requiring intervention, initial treatment of adult ITP is with corticosteroids, intravenous immunoglobulin, or intravenous anti-RhD immune globulin. These agents are rapid- acting but do not result in durable remissions in most patients. No corticosteroid has Keywords demonstrated superiority to others for ITP treatment. Subsequent treatment of adult ► platelets ITP is typically with thrombopoietin receptor agonists (TPO-RAs; romiplostim or ► immune eltrombopag), rituximab, or splenectomy. TPO-RAs are newer agents that offer an thrombocytopenia excellent response rate but may require prolonged treatment. The choice between ► diagnosis subsequent treatments involves consideration of operative risk, risk of asplenia, drug ► treatment side-effects, quality-of-life issues, and financial costs. Given the efficacy of medical ► corticosteroids therapies and the rate of spontaneous remission in the first year after diagnosis, ► intravenous splenectomy is frequently deferred in modern ITP treatment algorithms. Fostamatinib immunoglobulin (a tyrosine kinase inhibitor recently approved by the U.S. Food and Drug Administra- ► splenectomy tion) and several older immunosuppressive agents (azathioprine, cyclophosphamide, ► thrombopoietin cyclosporine, danazol, dapsone, mycophenolate mofetil, and the Vinca alkaloids) may receptor agonist be useful in patients with disease unresponsive to standard therapies or in specific ► rituximab clinical circumstances. This comprehensive review explores diagnostic considerations ► fostamatinib and surveys new and old treatment options for adults with ITP. Immune thrombocytopenia (ITP) is an autoimmune bleeding lation, while secondary ITP occurs in the setting of such a source disorder of excessive reticuloendothelial platelet destruction (e.g., systemic lupus erythematosus or chronic lymphocytic with inadequate compensatory platelet production. ITP results leukemia). Diagnosis of ITP remains clinical, as there is no This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. from the dual action of platelet autoantibodies that opsonize “gold standard” diagnostic test. Initial ITP treatment has platelets and induce megakaryocyte apoptosis as well as remained largely unchanged for several decades, with cortico- direct T cell–mediated megakaryocyte and platelet destruc- steroids and intravenous immunoglobulin (IVIG) typically used – tion.1 3 Modern definitionsofITPrequireaplateletcount< 100 to manage newly diagnosed patients and chronic patients  109/L for diagnosis in a patient with no other underlying requiring urgent rescue therapy.4,5 However, subsequent treat- causes for thrombocytopenia.4,5 Primary ITP occurs in the ment options have evolved considerably over the past decade. absence of a clinically identifiable source of immune dysregu- While most of the older treatments worked to reduce platelet published online Issue Theme Acquired Platelet Copyright © 2020 by Thieme Medical DOI https://doi.org/ December 12, 2019 Dysfunction—Laboratory and Clinical Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1700512. Implications; Guest Editors: Anne-Mette New York, NY 10001, USA. ISSN 0094-6176. Hvas, MD, PhD, Julie Brogaard Larsen, MD, Tel: +1(212) 760-0888. PhD, and Leonardo Pasalic, MBBS, PhD. 276 ITP: Modern Diagnosis and Treatment Al-Samkari, Kuter destruction via nonspecific action on the immune system, peripheral blood film, human immunodeficiency virus se- newer agents target more specifically the pathophysiology of rology, hepatitis C serology, and comprehensive metabolic ITP by improving platelet production or decreasing platelet panel (including transaminases, bilirubin, and alkaline phos- destruction. In this review, we will assess modern practices in phatase).5 The peripheral blood film should be examined to ITP diagnosis and treatment synthesizing the best available rule out evidence of other causes of thrombocytopenia as can evidence and expert opinion. be seen such as fragmented erythrocytes (suggesting throm- botic microangiopathy or disseminated intravascular coagu- Diagnosis of Immune Thrombocytopenia lation [DIC]) or atypical leukocytes (suggestive of myeloid or lymphoid malignancy). Giant platelets are frequently seen on Clinical Presentation peripheral blood film in ITP. Quantitative immunoglobulin The incidence of ITP is approximately 1 in 20,000 people and levels can be obtained in patients for whom a primary increases with age.6,7 It is slightly more common in females.7 immunodeficiency (e.g., common variable immunodeficien- The initial presentation of ITP is highly variable, from inci- cy) is suspected or prior to IVIG infusion but are not required dentally discovered asymptomatic mild thrombocytopenia in all patients.5 Bone marrow evaluation is not indicated to severe, life-threatening bleeding. Patients who present unless patients have additional unexplained cytopenia, a with profound thrombocytopenia (platelet count < 20  109/L significant family history of thrombocytopenia or myeloid and usually < 10  109/L) often have evidence of benign mu- malignancies, or poor response to typical initial treatment cocutaneous hemorrhage, such as petechiae, ecchymoses, and options (corticosteroids, IVIG, anti-D immune globulin).4,5 oral mucosal blood blisters. Though clinically benign, this While ELISA-based glycoprotein-specificdirectplateletau- frequently brings the patient to clinical attention. Significant toantibody testing has been repeatedly demonstrated to musculoskeletal bleeding, as occurs in severe coagulation have a high specificity in the > 80 to 90% range,12 it is not factor deficiencies, generally does not occur, but there is a recommended for routine diagnosis owing to its poor sensi- low, albeit important, risk of gastrointestinal bleeding and tivity.4,5 The sensitivity of platelet autoantibody testing for intracranial bleeding in profoundly thrombocytopenic ITP ITP diagnosis may be improved with adherence to recent patients. Bleeds may occur secondary to trauma, other pathol- laboratory platelet autoantibody testing guidelines,13 but ogy (such as a tumor), or spontaneously. Intracranial bleeding this remains under investigation. Other methods of platelet typically presents as intracerebral hemorrhage and is the most autoantibody testing, such as flow cytometric detection of common cause of ITP-related death, with a 50 to 80% mortality platelet-associated immunoglobulin G, are additionally not in patients > 60 years of age and up to 20% mortality in recommended.4,5 patients < 40 years of age.8,9 In a meta-analysis of 17 studies, Routine direct antiglobulin testing or testing for antinu- the rate of fatal bleeding in ITP was estimated at 0.0162 to clear antibodies, antiphospholipid antibodies, antithyroid 0.0389 cases per patient-year.9 Rapid-acting treatment mo- antibodies, or thyroid function is not recommended,4,5 dalities such as corticosteroids and IVIG are administered to although targeted testing may have utility in certain patients treat and prevent such serious bleeding complications in the given other medical history and findings on history and acute setting. physical examination. For example, direct antiglobulin test- While numerous factors impact the degree of thrombocy- ing is appropriate in patients with a concomitant anemia topeniathat is likely to causebleeding, most ITP patients do not with an elevated reticulocyte count or in those for whom present with mucocutaneous bleeding or clinically significant intravenous anti-RhD immune globulin is being considered hemorrhage until the platelet count is < 30  109/L and many for treatment. Routine testing for thrombopoietin (TPO) patients remain asymptomatic in the 20 to 29  109/L or even levels, reticulated platelets, bleeding time, serum comple- the 10 to 19  109/L range.7 The most common symptom in ITP ment, or platelet survival is similarly not recommended for aside from bleeding is fatigue, which occurs in 20 to 40% of diagnostic purposes.4,5 There may be a role of serum TPO in patients.10 Although the etiology is not entirely clear, fatigue predicting response to thrombopoietin receptor agonist can markedly affect quality of life in ITP patients and may even (TPO-RA) therapy,14 which is discussed in more detail later. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. be an indication for treatment, which may be very effective at alleviating fatigue.11 Classification of Immune Thrombocytopenia The chronicity of ITP has been defined according to the report Diagnostic Testing of the international ITP working group (IWG).15
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