TY - JOUR
T1 - Angiopoietin-2 is associated with sickle cell complications, including stroke risk, and decreases with hydroxyurea therapy.
AU - Siegert, Thomas
AU - Opoka, Robert
AU - Nakafeero, Maria
AU - Carman, Aubri
AU - Mellencamp, Kagan
AU - Latham, Teresa
AU - Hume, Heather
AU - Lane, Adam
AU - Ware, Russell
AU - Ssenkusu, John
PY - 2024/2/1
Y1 - 2024/2/1
N2 - 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, soluble endothelial selectin [sE-selectin], soluble intercellular cellular adhesion molecule 1, and soluble vascular endothelial cellular adhesion molecule) by enzyme-linked immunosorbent assay after initiation of hydroxyurea therapy. Samples were collected from Ugandan children with SCA enrolled in a clinical trial evaluating hydroxyurea vs placebo (NOHARM trial). Samples were collected at enrollment; and then after 2, 4, and 12 months of follow-up. Longitudinal changes in biomarker levels were evaluated using linear mixed effects models. Transcranial Doppler (TCD) velocities were measured at 10 to 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 < .05 for all). Hydroxyurea therapy at a fixed dose of 20 mg/kg per day decreased plasma angiopoietin-2, P-selectin, and sE-selectin levels over the study period (P < .05 for all). Angiopoietin-2 and sE-selectin were associated with higher TCD velocities. Mediation analysis suggests 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.
AB - 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, soluble endothelial selectin [sE-selectin], soluble intercellular cellular adhesion molecule 1, and soluble vascular endothelial cellular adhesion molecule) by enzyme-linked immunosorbent assay after initiation of hydroxyurea therapy. Samples were collected from Ugandan children with SCA enrolled in a clinical trial evaluating hydroxyurea vs placebo (NOHARM trial). Samples were collected at enrollment; and then after 2, 4, and 12 months of follow-up. Longitudinal changes in biomarker levels were evaluated using linear mixed effects models. Transcranial Doppler (TCD) velocities were measured at 10 to 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 < .05 for all). Hydroxyurea therapy at a fixed dose of 20 mg/kg per day decreased plasma angiopoietin-2, P-selectin, and sE-selectin levels over the study period (P < .05 for all). Angiopoietin-2 and sE-selectin were associated with higher TCD velocities. Mediation analysis suggests 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.
U2 - 10.1016/j.bvth.2024.100001
DO - 10.1016/j.bvth.2024.100001
M3 - Article
JO - Paediatrics and Child Health, East Africa
JF - Paediatrics and Child Health, East Africa
ER -