Abstract
Introduction Advances in the care of individuals with sickle cell disease (SCD) have led to increased survival to adulthood. Accelerated aging has been described in adults with SCD, characterized by age-related declines in hemoglobin (Hb), white blood cell count (WBC), and platelet count. These decreases in blood counts may occur due to bone marrow stress from ongoing inflammation, high hemolytic drive, and ineffective erythropoiesis, leading to bone marrow dysfunction as patients age. Hydroxyurea (HU), a current standard of care treatment for SCD, increases fetal hemoglobin and decreases inflammatory markers. Previously published studies evaluating age-related declines in blood counts have been cross-sectional studies of adult cohorts or were conducted before the widespread use of HU. With the increasing use of HU, evaluating the effect of HU on blood counts with increasing age is necessary to assess its long-term safety.
Methods In this retrospective cohort study, we included participants with SCD enrolled in the Sickle Cell Clinical Research and Intervention Program (SCCRIP, NCT02098863), a lifespan cohort study for SCD. We conducted cross-sectional analyses of blood count measurements from individuals grouped by genotypes: HbSS/HbSβ0thalassemia (SS/Sβ0) and HbSC/Sβ+thalassemia (SC/Sβ+), across age groups and stratified into 0-9 years, 10-19 years, 20-29 years, 30-39 years, and ≥40 years. Within the entire cohort, we also compared age-stratified blood counts in patients with SS/Sβ0and SC/Sβ+who received HU and those who did not, after excluding individuals who received monthly blood transfusions. Descriptive statistics by age group included mean ± SD, medians, count, and percentages. Groups were compared using Kruskal-Wallis tests or ANOVA for continuous variables and Fisher's exact test for categorical variables.
Results The entire cohort included individuals with SS/Sβ0 (n = 907; female = 49%) and SC/Sβ+ (n = 526; female = 53%), with median ages of 16.7 (range: 0.7, 72.2) and 16.4 (range: 0.6, 65.0) years, respectively. Eighty-five percent of individuals with SS/Sβ0 and 29% with SC/Sβ+ were receiving HU. Cross-sectional analysis of the entire cohort showed lower Hb and platelet counts with increasing age, in both the SS/Sβ0 and SC/Sβ+ groups. The mean WBC count decreased with age only in the SC/Sβ+ group.
In patients with SS/Sβ0 receiving HU, Hb (p = 0.48) and WBC counts (p = 0.08) were similar across the age groups. In patients not receiving HU, WBC (p = 0.04) and Hb (p = 0.05) levels decreased with increasing age. However, platelet counts were lower with increasing age, regardless of whether patients were on HU.
In SC/Sβ+ patients, WBC counts (p = 0.45) and platelet counts (p = 0.84) were similar across the age groups among those receiving HU; WBC counts (p = 0.007) and platelet counts (p = 0.0004) were significantly lower with increasing age in patients not receiving HU. Hb levels decreased with increasing age in patients on HU, but no age-related changes were observed in patients not on HU.
Conclusion HU does not appear to worsen cytopenia with increasing age in individuals with SCD. Older patients with SS/Sβ0 on HU had higher Hb compared to those not on HU. While a lower WBC count was observed in patients with SS/Sβ0 and SC/Sβ+ receiving HU, no age-related decline in WBC count was noted on HU. Prospective studies evaluating the trajectory of blood counts and examining the impact of both dosage and duration of HU on cytopenias throughout the lifespan are needed.
