Effect of Hydroxyurea on Elevated Pulmonary Artery Pressures in Children with Sickle Cell Disease

Pulmonary hypertension (PHT) is a significant complication of sickle cell disease. Studies in children report a 16–30% prevalence of elevated pulmonary artery pressures, as estimated by measurement of tricuspid regurgitant jet velocity (TRV) on echocardiography. The pathogenesis of elevated pulmonary artery pressures is multifactorial, with hemolysis induced endothelial dysfunction playing a major role. More recent studies highlight the role of inflammation in the pathogenesis. Hydroxyurea is a well established treatment for sickle cell disease. It acts primarily by induction of fetal hemoglobin, thereby reducing hemolysis, with possible additional effects on vascular and endothelial function. The aim of this study was to determine if early detection and treatment with hydroxyurea will decrease elevated pulmonary artery pressures in children with sickle cell disease.

The study was conducted at 3 centers. Children with Hb SS and Hb Sb0 thalassemia between the ages of 5–21 years, with a screening echocardiogram showing a TRV ≥ 2.5 m/sec were identified. An echocardiogram was repeated to confirm elevated TRV. Subjects with persistent elevation of TRV ≥ 2.5 m/sec on repeat echocardiogram, were consented and started on hydroxyurea at 20 mg/kg/d with escalation to a maximum tolerated dose or a total daily dose of 30 mg/kg/d. Laboratory data and echocardiograms were repeated at 6 and 12 months to measure effect of hydroxyurea on TRV. Additionally blood and urine samples were also collected pre treatment, at 6 and 12 months post treatment for biomarker analysis, which will be performed later. Baseline and 6 month laboratory and echocardiogram data were compared using paired t test.

Twelve patients were enrolled. Mean age was 12.25 years (range 6–19 years) with a M:F ratio of 2:1. Average follow up is 11 months. Patients tolerated hydroxyurea well, and in 90% of patients the dose was escalated to 30 mg/kg/d. 1 patient achieved MTD at 20 mg/kg/d. Two patients went off study at 4 and 5 months respectively.

As shown in Table 1, six months after starting hydroxyurea there was a significant increase in mean oxygen saturation, hemoglobin, mean corpuscular volume and fetal hemoglobin. There was a significant decrease in mean reticulocyte count, LDH and white blood cell count. There was no significant change in TRV six months after treatment with hydroxyurea.

Hydroxyurea significantly decreased measures of hemolysis in children with sickle cell disease. Six months after treatment with hydroxyurea, there was no significant change in estimated pulmonary artery pressures measured on echocardiography. The study is ongoing to see if hydroxyurea affects pulmonary artery pressures with a longer duration of treatment.

No relevant conflicts of interest to declare.