Angiopoietin-2 is associated with sickle cell complications including stroke risk and decreases with hydroxyurea therapy

Hydroxyurea reduces morbidity and mortality in children with sickle cell anemia (SCA). The endothelium is central to SCA-related complications including stroke. However, hydroxyurea’s impact on the endothelium is not well described. To address this gap, we measured plasma levels of endothelial activation markers (angiopoietin-2, P-Selectin, sE-Selectin, sICAM-1, sVCAM-1) by ELISA following initiation of hydroxyurea therapy. Samples were collected from Ugandan children with SCA enrolled in a clinical trial evaluating hydroxyurea versus placebo (NOHARM, ClinicalTrials.gov: NCT01976416). Samples were collected at enrollment, and then after 2-, 4- and 12-months follow-up. Longitudinal changes in biomarkers levels were evaluated using linear mixed effects models. Transcranial Doppler (TCD) velocities were measured at 10-12 months follow-up to assess cerebral blood flow and primary stroke risk. Mediation analysis was used to explore causal pathways of hydroxyurea-mediated effects on TCD velocities. In total, 798 plasma samples were tested from 205 children (mean enrollment age: 2.2 years). At enrollment, higher levels of angiopoietin-2 were associated with a previous medical history of dactylitis, vaso-occlusive crises, acute chest syndrome, and transfusion (p<0.05 for all). Hydroxyurea therapy at a fixed dose of 20 mg/kg/day decreased plasma angiopoietin-2, P-Selectin, and sE-Selectin levels over the study period (p<0.05 for all). Angiopoietin-2 and sE-Selectin were associated with higher TCD velocities. Mediation analysis suggested that hydroxyurea decreases TCD velocities through an increase in fetal and total hemoglobin. Increased fetal and total hemoglobin, and decreased white blood cell count may decrease TCD velocity in part through an angiopoiten-2 mediated pathway.