In Focus
Immune Thrombocytopenia
A hematological autoimmune disorder with various clinical manifestations
Immune thrombocytopenia (ITP) is the most common hematological autoimmune disorder caused by immune-mediated destruction of platelets and megakaryocytes (MKs) that can lead to bleeding, fatigue and a probability of thrombosis1-4. The disease can manifest in both children and adults, with distinct clinical presentations and underlying causes.
Pathophysiology
In primary ITP, which is the most common form, the exact cause remains unclear, but it is believed to result from an aberrant immune response. In this condition, the immune system recognizes platelet antigens as foreign and initiates the production of autoantibodies and cytotoxic T cells that target and destroy them, particularly in the spleen. In addition, the autoimmune lymphocytes can migrate into the BM and destroy MKs leading to platelet production defects5. The pathophysiology of ITP is complex and involves significant dysregulation of the immune system, leading to the destruction of platelets and MKs. While the exact cause of ITP remains unclear, in many cases, several key mechanisms have been identified. For example, one of the central features of ITP is the production of IgG autoantibodies, that target platelet surface antigens. These antibodies bind to platelet glycoproteins, such as glycoprotein IIb/IIIa (GPIIb/IIIa) and glycoprotein Ib/IX (GPIb/IX), forming immune complexes3,6,7. These immune complexes trigger platelet destruction through various mechanisms, including complement activation and phagocytosis by macrophages and monocytes, primarily in the spleen.
CD4+ and CD8+ T cells
In addition, the autoantibody production is intimately linked with abnormal T cell responses, particularly CD4+ T-helper (Th) 1 and Th17 cells that can release pro-inflammatory cytokines, such as interferon-gamma (IFN-γ) and interleukin (IL)-17, which can promote immune responses and contribute to platelet destruction3,5,6. Furthermore, CD8+ cytotoxic T cells (CTL) also recognize platelet antigens that are presented on the surface of antigen-presenting cells (APCs)3,8. Activated CTL can produce pro-inflammatory cytokines, that promote inflammation and immune responses, potentially exacerbating the autoimmune reaction against platelets. CTLs can also directly bind and cause destruction of platelets and MKs3,9. There is growing recognition of the role of immunosuppressive mechanisms in regulating the disease. These mechanisms include, for example, CD4+ regulatory T cells (Tregs), regulatory B cells (Bregs), tolerogenic APC, checkpoint inhibitors and various soluble immune regulatory molecules.
Diagnosis
The diagnosis of ITP involves a thorough medical history, physical examination, and blood tests such as a CBC and a peripheral blood smear1,2. In recent decades there has been a clear positive development in tests for detecting platelet autoantibodies as a diagnostic for ITP. While so-called 'whole platelet' assays were initially used, more recently there has been a switch to 'glycoprotein-specific' assays. This has resulted in an increase in specificity from 50% to more than 95% respectively. The sensitivity has also increased, but unfortunately only up to a maximum of 80% 7,10. ITP can manifest in various ways, and its severity can vary from person to person. Common symptoms of ITP include easy bruising, petechiae, nosebleeds, and prolonged or excessive bleeding from minor cuts or injuries1,2. In severe cases, individuals with ITP may experience more serious bleeding episodes, such as gastrointestinal bleeding or intracranial hemorrhage, which can be life-threatening. In conclusion, it is advisable to carefully evaluate the impact of these methods on specific cell types and intended experimental outcomes. Researchers and manufacturers must consider these factors when selecting the appropriate pathogen reduction method for hPL. They need to strike a balance between ensuring safety by eliminating pathogens and preserving the beneficial biological properties of hPL for its intended applications.
ITP Management
The management of ITP depends on the severity of the condition and its impact on the patient's daily life. Mild cases of ITP may not require immediate treatment and can be monitored closely1,2. However, if treatment is necessary, several options are available including corticosteroids such as prednisone, Intravenous Immunoglobulin (IVIG), Immunosuppressive therapy such as rituximab and/or azathioprine, thrombopoietin receptor agonist (TPO-Ras), and splenectomy4. Despite ITP’s complexity, advances in medical research and treatment options have improved the outlook for individuals living with ITP. Early diagnosis, appropriate medical management, and ongoing monitoring by healthcare professionals are essential for ensuring the well-being of those affected by this condition. Continued research into the pathogenesis of ITP promises new insights and therapeutic strategies that will further enhance the quality of life for individuals battling this rare autoimmune disorder.
Figure 1. Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by low platelet counts.
References
- Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood advances. 2019;3:3829-66.
- Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3:3780-817.
- Zufferey A, Kapur R, Semple JW. Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP). Journal of Clinical Medicine. 2017;6.
- Provan D, Semple JW. Recent advances in the mechanisms and treatment of immune thrombocytopenia. EBioMedicine. 2022;76:103820.
- Audia S, Mahévas M, Nivet M, Ouandji S, Ciudad M, Bonnotte B. Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments. Hemasphere. 2021;5:e574.
- Audia S, Mahévas M, Samson M, Godeau B, Bonnotte B. Pathogenesis of immune thrombocytopenia. Autoimmunity reviews. 2017;16:620-32.
- Porcelijn L, Huiskes E, Oldert G, Schipperus M, Zwaginga JJ, de Haas M. Detection of platelet autoantibodies to identify immune thrombocytopenia: state of the art. British journal of haematology. 2018;182:423-6.
- McKenzie CG, Guo L, Freedman J, Semple JW. Cellular immune dysfunction in immune thrombocytopenia (ITP). British journal of haematology. 2013;163:10-23.
- Olsson B, Andersson PO, Jernås M, Jacobsson S, Carlsson B, Carlsson LM, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med. 2003;9:1123-4.
- Porcelijn L, Schmidt DE, Oldert G, Hofstede-van Egmond S, Kapur R, Zwaginga JJ, de Haas M. Evolution and Utility of Antiplatelet Autoantibody Testing in Patients with Immune Thrombocytopenia. Transfus Med Rev. 2020 Oct;34(4):258-269.
