Extracellular Vesicles in Beta-Thalassemia: Phenotype-Specific Profiles and Potential Clinical Associations.

Βeta-thalassemia is one of the most common genetic disorders worldwide, characterized by ineffective erythropoiesis (IE), which leads to a wide spectrum of heterogeneous disease-related complications. Extracellular vesicles (EVs) have emerged as having important roles in β-thalassemia complications; however, phenotype-specific differences and their relevance to clinical outcomes remain incompletely defined. This review addresses the knowledge gap with regards to the difference in  EV profiles between transfusion-dependent β-thalassemia (TDT) and nontransfusion-dependent β-thalassemia (NTDT), and how these may contribute to distinct disease manifestations. The evidence indicates that EVs derived from platelets, erythrocytes, leukocytes, and endothelial cells are elevated in β-thalassemia, with phenotype-specific patterns. TDT is predominantly characterized by EV profiles associated with transfusion exposure and iron overload, whereas NTDT shows EV alterations linked to IE, chronic hemolysis, and endothelial activation. These processes have been implicated in thrombosis, pulmonary hypertension (PHT), vascular injury, and various organ dysfunctions. These findings are also supported by functional in vitro studies that thalassemic EVs can induce endothelial activation, oxidative stress, and altered cellular proliferation. Moreover, splenectomy emerges as an important modifier of EV profiles, with splenectomized patients consistently demonstrating higher levels of procoagulant EVs, potentially contributing to increased thrombotic risk. However, heterogeneity in study design, transfusion exposure, and therapeutic interventions complicates interpretation. Overall, this review highlights phenotype-specific differences in EVs between TDT and NTDT and summarizes proposed mechanisms linking EVs to clinical complications. For future perspective, well-characterized cohort studies incorporating rigorous EV isolation, quantitative synthesis, and longitudinal design are needed to clarify the clinical utility of EVs in β-thalassemia.