Endothelial Dysfunction in β-Thalassemia: Mechanisms, Biomarkers, Vascular Imaging and Therapeutic Perspectives

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Background/Objectives: Endothelial dysfunction is increasingly recognized as a key contributor to vascular complications in β-thalassemia but remains insufficiently integrated into clinical assessment and therapeutic trial design. This review summarizes current evidence on the mechanisms, biomarkers, vascular imaging findings, and therapeutic perspectives of endothelial dysfunction across the clinical spectrum of β-thalassemia. Methods: A focused PubMed search was conducted using predefined terms related to endothelial dysfunction, nitric oxide, oxidative stress, adhesion molecules, extracellular vesicles, vascular imaging, and therapeutics in β-thalassemia. Original studies and systematic reviews evaluating endothelial dysfunction, vascular biomarkers, imaging, or cardiovascular outcomes in β-thalassemia were included. Results: Endothelial dysfunction arises from the interplay of hemolysis-driven nitric oxide depletion, free heme- and iron-mediated oxidative injury, chronic inflammation, extracellular vesicle-mediated vascular activation, and hypercoagulability. Meta-analyses demonstrate significant elevations in intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, P-selectin, and endothelin-1. Emerging biomarkers include endothelial activation and stress index, adipocytokines, and serum metabolomics. Vascular imaging demonstrates impaired flow-mediated dilation, increased carotid intima-media thickness, elevated pulse-wave velocity, and pulmonary hypertension, with distinct vascular phenotypes in transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Iron chelation, luspatercept, mitapivat, and curative gene-based therapies have strong biological rationale for improving endothelial function, although vascular endpoints have rarely been evaluated. Conclusions: Endothelial dysfunction is a multidimensional and potentially modifiable component of β-thalassemia vasculopathy. Future clinical trials should incorporate standardized endothelial biomarkers and vascular imaging as predefined endpoints and evaluate TDT and NTDT separately to advance mechanism-based vascular therapies.

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