Association of Endothelial Dysfunction and Angiogenesis in Patients with Thalassemia Intermedia

Angiogenic growth factors, such as the vascular endothelial growth factor (VEGF) family of proteins, govern numerous aspects of vessel homeostasis. Placental growth factor (PlGF) is a member of the VEGF family of angiogenic proteins and is expressed in placental, cardiac, and lung tissue. Placental growth factor (PlGF) and its receptor the fms-like tyrosine kinase receptor 1 (Flt-1 or VEGF-R1) are novel therapeutic targets for angiogenic disorders. These growth factors exert pleiotropic effects, potentially beneficial, such as the promotion of angiogenesis, and/or potentially harmful pro-inflammatory effects, such as the promotion of endothelial dysfunction and pulmonary hypertension. von Willebrand factor (vWF) has been proposed as a biomarker of endothelial damage/dysfunction because increased plasma levels have been found in inflammatory and atherosclerotic vascular diseases and is defined as a novel link between hemostasis and angiogenesis.

Patients and Methods: We investigated if alterations in angiogenic growth factors may contribute to endothelial dysfunction in patients with thalassemia intermedia (TI) using peripheral biomarkers. Thirty-four adult patients with TI were included in the study, while 20 healthy individuals served as controls. Markers of inflammation such as high-sensitivity C-reactive protein (hs-CRP) and serum Amyloid A protein (SAA), along with markers of endothelial dysfunction such as von Willebrand factor and nitric oxide (NO) and angiogenesis such as PlGF and soluble Flt-1 (sFlt-1) were measured in patients and controls by means of nephelometric, colorimetric and electrochemiluminescence immunoassays, while tissue hypoxia was evaluated in terms of hemoglobin oxygen affinity (P₅₀).

The main results of the study showed that: a) plasma levels of vWF, NO, PlGF and sFlt-1 were significantly higher in patients with TI compared to controls (88.0±21.8 vs 71.1±21.5 IU/dL, 101.5±34.7 vs 52.1±8.2 mmol/L, 52.2±20.0 vs 17.2±4.0 pg/mL and 96.5±25.2 vs 76.8±11.5 pg/mL, respectively (p<0.01), while angiogenic balance expressed as sFlt-1/PlGF was significantly lower in patients with TI compared to controls (p<0.0001), b) in patients with TI the plasma levels of vWF correlated significantly with: NO (r=0.535, p<0.001), PlGF (r=0.478, p=0.004) and sFlt-1 (r=0.609, p<0.0001), while no associations were found between vWF with Hb and Hb F levels and c) both PlGF and sFlt-1 levels correlated significantly with NO levels (r=0.571, p<0.001 and r=0.482, p=0.004, respectively) and d) sFlt-1/PlGF correlated significantly with Hb F levels (r=0.385, p=0.02) and with P₅₀ values (r=0.365, p<0.05).

These results demonstrate for first time the important link between endothelial dysfunction and angiogenesis in patients with TI. τhe decreased sFlt-1/PlGF ratio in almost all patients with TI suggests that the pro- and anti-angiogenic system is shifted towards the pro-angiogenic state, providing evidence that the factors contributing in this dysregulation are low-grade inflammation and tissue hypoxia.

No relevant conflicts of interest to declare.