Immune Thrombocytopenia (ITP)


Immune thrombocytopenia (ITP) is an acquired autoimmune condition in which blood platelet levels are abnormally low. Platelets are essential for blood clotting and healing. Low platelet counts increase the risk for bleeding, most commonly as minor mucocutaneous bleeding. Rarely in ITP, episodes of severe, life-threatening bleeding occur, including intracranial and gastrointestinal hemorrhage.1,2  

Pathophysiology of Platelet Destruction

In ITP, the immune system, for unknown reasons, produces immunoglobulin G autoantibodies, also called antiplatelet antibodies, that target normal platelets. The autoantibodies bind specifically to proteins (predominantly glycoproteins IIb/IIIa and Ib/IX) on the surface of platelet cell membranes.3 

After the platelets are covered by autoantibodies, they are sequestered in the spleen, where they undergo phagocytosis by mononuclear macrophages, which recognize them as foreign substances and tag them for destruction.4 The key mediators that drive platelet clearance in the spleen include Fcγ receptors RIIA and RIIIA and low-affinity receptors, which allow macrophages to bind to the autoantibody-platelet complexes.3,5 As a result, the number of platelets circulating in the blood is decreased.4

Complement activation results in the deposition of complement 3b (C3b) on the surface of platelets, which binds to complement receptor 1 (CR1). This process promotes mononuclear macrophage phagocytosis of opsonized platelets in the spleen.5

Splenic macrophages activate autoreactive CD4 T cells; these interact with autoreactive B cells, stimulating their proliferation and differentiation into plasma cells and the synthesis of antiplatelet antibodies.1,5 Patients with ITP present with leukocyte abnormalities.6

Studies increasingly are confirming the role of dendritic cells in the pathogenesis of ITP. Dendritic cells present antigens and stimulate T cells against these antigens.6

Researchers in one study analyzed the blood of 32 patients with ITP, discovering that dendritic cells stimulated CD4-positive and CD25-negative T-cell proliferation while simultaneously inhibiting regulatory T cells (Tregs), which are involved in suppressing the immune response. Treg suppression correlated with increased levels of proinflammatory cytokines, such as interleukin-2 (IL-2) and interferon gamma (IFNG), and decreased levels of interleukin-10 (IL-10).5,6 Decreased numbers of regulatory B cells (Bregs) have also been documented in pediatric patients with ITP.6

These new findings regarding the dysregulation of B cells, T cells, and dendritic cells may result in the development of antigen-specific therapies that target the autoimmune tolerance mechanisms contributing to ITP pathophysiology.6

Read more about ITP experimental therapies

Pathophysiology of Megakaryocyte Dysfunction

In ITP, low platelet levels are a consequence not only of the active, premature destruction of functional platelets by autoantibodies but also of insufficient platelet production by megakaryocytes to compensate for platelet destruction. ITP affects megakaryocytes in bone marrow, which are responsible for platelet production. This also leads to a decreased number of circulating platelets. Biopsy of patients with ITP in the absence of other significant abnormalities shows a normal to increased number of megakaryocytes.4 

Megakaryocytes in the bone marrow express glycoproteins similar to those of platelets, so the autoantibodies that target platelets in ITP also target megakaryocytes. As a result, their capacity to increase platelet production and maintain sufficient levels in the circulation is impaired.5

Read more about ITP etiology

Primary vs Secondary ITP

ITP is classified according to its duration as newly diagnosed (0-3 months), persistent (3-12 months), or chronic (>12 months).7 

ITP is also classified as either primary or secondary. Primary ITP occurs in the absence of underlying or triggering conditions, whereas secondary ITP manifests in response to an underlying condition, such as viral or bacterial infection, hematologic or other type of malignancy, vaccination, another autoimmune condition, or drug-induced thrombocytopenia. Both primary and secondary ITP are characterized by the formation of self-reacting antiplatelet antibodies, but they differ in respect to pathogenesis.7 

Comparative analysis of primary vs secondary ITP revealed a higher prevalence of secondary ITP with a positive correlation to advancing age. Patients demonstrated an increased bleeding tendency in primary ITP with lower platelet count.7 

In secondary ITP, autoantibody formation is stimulated when an underlying infection or condition cross-reacts with platelet antigens and causes immune complexes to bind to platelet Fcγ receptors. Infections include those caused by HIV, hepatitis B or C virus, Epstein-Barr virus, cytomegalovirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Helicobacter pylori. Other underlying conditions that may trigger ITP include Evans syndrome, lymphoproliferative disorders, lupus, and primary immunodeficiency syndromes.5,7 

Read more about ITP comorbidities

References

  1. Stasi R. Pathophysiology and therapeutic options in primary immune thrombocytopenia. Blood Transfus. 2011;9(3):262-273. doi:10.2450/2010.0080-10
  2. Arnold DM. Bleeding complications in immune thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2015;2015:237-242. doi:10.1182/asheducation-2015.1.237
  3. Kessler CM. Immune thrombocytopenia (ITP): etiology. Medscape. Updated January 7, 2021. Accessed October 30, 2022.
  4. Kessler CM. Immune thrombocytopenia (ITP): practice essentials. Medscape. Updated January 7, 2021. Accessed October 30, 2022.
  5. Audia S, Mahévas M, Nivet M, Ouandji S, Ciudad M, Bonnotte B. Immune thrombocytopenia: recent advances in pathogenesis and treatments. HemaSphere. 2021;5(6):e574. doi:10.1097/HS9.0000000000000574
  6. Semple J, Rebetz J, Maouia A, Kapur R. An update on the pathophysiology of immune thrombocytopenia. Curr Opin Hematol. 2020;27(0):1-7. doi:10.1097/MOH.0000000000000612
  7. Sultan S, Ahmed SI, Murad S, Irfan SM. Primary versus secondary immune thrombocytopenia in adults; a comparative analysis of clinical and laboratory attributes in newly diagnosed patients in Southern Pakistan. Med J Malaysia. 2016;71(5):269-274.

Reviewed by Debjyoti Talukdar, MD, on 10/30/2022.

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