•Patients with chronic ITP had clonal expansions of disease-associated TEMRA CD8+ T cells.•CD8+ T cells bind to platelets and cause their activation and apoptosis, defining an antibody-independent mechanism of platelet destruction. Display omitted Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multidimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterized patients with ITP and compared them with age-matched controls using immunophenotyping, next-generation sequencing of T-cell receptor (TCR) genes, single-cell RNA sequencing, and functional T-cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L−) expressing intracellular interferon gamma, tumor necrosis factor α, and granzyme B, defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the TCR showed expanded T-cell clones in patients with ITP. T-cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP. The importance of cytotoxic T cells has been recognized in chronic immune thrombocytopenia (ITP), yet how CD8+ T cells evolve and perpetuate chronic ITP is a mystery. This month’s CME article, a Plenary Paper by Malik and colleagues, demonstrates that in chronic ITP, there is clonal expansion of a particular subset of CD8+ T cells, known as terminally differentiated effector memory T cells, which persist over years, are more evident in refractory ITP, and are more prevalent when the platelet count is low. Furthermore, CD8+ T cells induce platelet activation and apoptosis in an antibody-independent mechanism for refractory thrombocytopenia that may be amenable to therapeutic targeting.