Immune thrombocytopenia: Evolving mechanistic understanding and clinical development of new therapies

A BSTRACT Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia resulting from increased platelet destruction, impaired platelet production, or both. Once viewed primarily as a benign, antibody-mediated condition, ITP is now recognized as a heterogeneous immune dysregulation syndrome involving autoreactive lymphocytes, innate immune activation, complement engagement, and megakaryocytic dysfunction. Although corticosteroids, intravenous immunoglobulin, anti-D immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists have constituted the therapeutic foundation for decades, these approaches remain limited by transient responses, toxicity, and insufficient disease modification. Advances in immunopathology have catalyzed the development of targeted therapeutics designed to interrupt discrete mechanisms underlying platelet destruction or impaired thrombopoiesis. Bruton tyrosine kinase (BTK) inhibitors (rilzabrutinib and orelabrutinib) modulate B-cell activation and macrophage effector pathways; spleen tyrosine kinase inhibitors (fostamatinib) block Fcγ receptor-mediated phagocytosis, neonatal Fc receptor inhibitors (efgartigimod and rozanolixizumab) accelerate IgG catabolism and rapidly reduce pathogenic autoantibody burden; and complement inhibition (sutimlimab) provides a rational strategy for patients in whom classical pathway activation contributes to refractory disease. Collectively, these agents represent the most significant expansion of the ITP treatment landscape in decades, offering steroid-sparing options and enabling more durable, individualized disease control. As ITP management transitions toward mechanism-based, biomarker-informed approaches, understanding the immunologic underpinnings of emerging therapies will be essential for optimizing treatment sequencing, improving long-term outcomes, and advancing personalized care for patients with this complex autoimmune disorder.