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The precise mechanisms leading to platelet-targeted autoimmunity in immune thrombocytopenia (ITP) are not known. Cellular checkpoints normally regulate immunological self-reactivity during the development of B and T cells through cell deletion, receptor editing, induction of anergy, and extrinsic cellular suppression. When these checkpoints fail, tolerance to self-antigens may be lost. In this review, we summarize the various immune mechanisms contributing to the development of ITP and relate them back to the checkpoint model of autoimmunity. These mechanisms, including increased levels of lymphocyte growth factors, resistance to death signals, and loss of T-regulatory function, result in an environment permissive to the development of platelet-reactive B and T cells. The mechanisms that lead to thrombocytopenia once tolerance for platelet antigens is lost are examined, including complement-dependent and apoptotic pathways. An improved understanding of ITP pathogenesis will ultimately guide the development of better therapies.