The Immune System in the Pathophysiology of ITP

Primary and Secondary ITP

Immune thrombocytopenia represents an autoimmune disease characterized by a low platelet count and an increased tendency to bleed. ITP is a diagnosis that assumes the exclusion of other causes of platelet decline. In cases of unclear triggering mechanisms, it is referred to as primary ITP; in the presence of another autoimmune disease, lymphoproliferation, or in connection with infections, transfusions, or medications, it is termed secondary ITP.

Immunity and ITP

From the perspective of the initiating event leading to anti-platelet autoimmunity, we do not know a clear connection, but strong evidence suggests that autoantibodies and autoreactive CD8⁺ cytotoxic T lymphocytes trigger increased platelet destruction and disrupt platelet production by megakaryocytes in the bone marrow.

Approximately 60% of all patients with ITP can be identified with autoantibodies, predominantly against platelet glycoprotein IIb/IIIa or the glycoprotein Ib-IX-V complex. Autoantibodies accelerate platelet removal in the spleen through macrophages and dendritic cells. They also affect platelet apoptosis or inhibit platelet production from megakaryocytes.

In most patients with ITP, B lymphocytes targeting platelets can be found. However, it is assumed that mechanisms independent of B lymphocytes also exist, such as CD8⁺ T lymphocytes targeting platelet production by megakaryocytes in the bone marrow. CD4⁺ helper T lymphocytes are important for the differentiation of B lymphocytes into plasma cells producing autoantibodies. Regulatory T lymphocytes are necessary for ensuring immune tolerance, and loss of tolerance contributes to the development of chronic ITP. Infections may lead to exposure of antigens on the surface of platelets.

The Importance of Thrombopoietin

Every day, about 100 billion platelets are produced in the body from the cytoplasmic blebbing of bone marrow megakaryocytes. Platelets then circulate for approximately 7–10 days. The key hormone for platelet production is thrombopoietin (TPO), synthesized in the liver, which stimulates the formation of megakaryocytes via its receptor. In the case of ITP, this normal life cycle of platelets is disrupted by the presence of autoantibodies and autoreactive T lymphocytes, which interfere with both platelet production and their clearance. Patients with ITP exhibit a slightly elevated TPO level, likely because platelets bound with TPO are quickly removed.

For this reason, one of the therapeutic options for ITP is the stimulation of TPO receptors on megakaryocytes using their agonists (TPO-RA), which has been shown to be an effective approach for many patients. However, the fact that not all patients respond to TPO-RA highlights the complexity of inducing a treatment response.

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Source: Swinkels M., Rijkers M., Voorberg J. et al. Emerging concepts in immune thrombocytopenia. Front Immunol 2018; 9: 880, doi: 10.3389/fimmu.2018.00880.