Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

Abstract

Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by low platelet counts. The pathogenesis of ITP remains unclear although both antibody-mediated and/or T cell-mediated platelet destruction are key processes. In addition, impairment of T cells, cytokine imbalances, and the contribution of the bone marrow niche have now been recognized to be important. Treatment strategies are aimed at the restoration of platelet counts compatible with adequate hemostasis rather than achieving physiological platelet counts. The first line treatments focus on the inhibition of autoantibody production and platelet degradation, whereas second-line treatments include immunosuppressive drugs, such as Rituximab, and splenectomy. Finally, thirdline treatments aim to stimulate platelet production by megakaryocytes. This review discusses the pathophysiology of ITP and how the different treatment modalities affect the pathogenic mechanisms.

Keywords: immune thrombocytopenia (ITP); B cells; T cells; autoimmunity; platelets.

Figure 1

Cellular pathogenic mechanisms in immune thrombocytopenia (ITP). Multiple cells are involved in the pathogenesis of ITP. B cells and plasma cells are abnormally regulated and produce autoantibodies, which bind platelets and megakaryocytes (MKs), inducing their impairment and/or degradation in the spleen and liver. The cellular immune response is also affected, leading to a decrease of Tregs and Bregs, which contributes to autoreactive plasma cell survival (supporting autoantibody production) and unbalanced Th CD4⁺ T cell subsets. Moreover, cytotoxic CD8⁺ T cells are also activated, inducing platelet and MK apoptosis as well as the dysregulation of BM niche homeostasis. Therefore, ITP pathogenesis does not only results in platelet destruction, but also in a megakayopoiesis and thrombopoiesis defect.

Figure 2

Therapeutic mechanisms of current ITP treatments. Several drugs are used to treat chronic ITP. The first line of treatment consists of corticosteroids alone or in combination with intravenous immunoglobulin (IVIg) or anti-D, which aim to decrease platelet destruction and platelet antigen presentation by antigen presenting cells (APC) to restore a normal immune response. They also act on B cells and plasma cells, thus decreasing autoantibody production, and rescue impaired Treg function. Second-line therapies include immunosupressive drugs such as Rituximab, which directly targets B cells, and splenectomy. Both treatments also modulate the T cell compartment, notably increasing Tregs. Thrombopoietin (TPO)-receptor agonists (Romiplostim and Eltrombopag), which stimulate platelet production by MKs, are third-line treatments and are used for patients who do not respond to other therapies. Here again, TPO-agonists present indirect immunomodulatory effects on Bregs and Tregs. Combining multiple therapeutic approaches is often required to ensure the restoration of a physiological platelet count.