The integrated stress response in immune thrombocytopenia: from cellular stress to hematopoietic adaptation

Immune thrombocytopenia (ITP) is an autoimmune hematologic disorder characterized by immune-mediated platelet destruction and impaired platelet production. In addition to these core abnormalities, ITP is associated with persistent inflammation, metabolic disturbance, oxidative injury, and altered proteostasis in immune cells, megakaryocytes, platelets, and the bone marrow microenvironment. In this narrative review, we examine whether the integrated stress response (ISR) could provide a mechanistic link between these stress phenotypes and cell-specific responses in ITP. Evidence for the involvement of the four canonical eIF2α kinases is uneven and varies substantially by cell type and experimental setting. We therefore propose a cell-specific hematopoietic response model in which sustained stress inputs interact with the distinct response capacities of immune and hematopoietic cell populations. From a therapeutic perspective, we discuss current ITP treatments in terms of their established immunological or hematopoietic actions and distinguish these primary effects from secondary changes in cellular stress that may follow disease control. We also refer to some experimental methods to confirm the participation of ISR. By emphasizing these differences, the review intends to promote future mechanistic research and the assessment of possible therapeutic strategies related to stress.