Sickle Cell Anemia (SCA) is a rare, devastating, and debilitating disease marked by the pathophysiologic features of hemolytic anemia, vaso-occlusion, and progressive end-organ damage. The most devastating complication of pediatric SCA is the development of central nervous system events such as overt stroke or silent cerebral infarcts (SCIs) which can produce significant physical and neurocognitive deficits. Transcranial Doppler ultrasonography (TCD) measures cerebral artery blood flow velocity in children with SCA. Elevated TCD velocity levels are a reliable predictor of stroke risk, and children with conditional TCD levels (defined as > 170 to < 200 cm/sec) are at increased risk of stroke compared to those with normal TCD levels (<170 cm/sec). Practice guidelines recommend patients with conditional TCD levels undergo frequent periodic TCDs; however, no standard-of-care therapy is recommended for reduction of stroke risk. Anemia has been shown to be associated with increased risk of stroke, SCI, and abnormal TCD levels (>200 cm/sec), but the extent to which hemoglobin (Hb) concentration influences TCD level elevation is unknown. Using recently collected longitudinal, real world data, this study sought to quantify the impact of the rise in Hb obtained during hydroxyurea (HU) therapy on the change observed in TCD levels as an estimate for the magnitude of Hb rise that would be predicted to convert an individual from the conditional TCD level range (moderate risk of stroke) to the normal TCD level (low risk of stroke).


Children (age <16 years) with HbSS or HbSβ0-thalassemia (SCA) in the Sickle Cell Clinical Research and Intervention Program (SCCRIP, Pediatr Blood Cancer. 2018 Sep;65(9):e27228, IRB approved, participants consented), a longitudinal lifetime cohort study for individuals with SCD and who initiated HU before Dec 31, 2017, were included. Patients on chronic red blood cell transfusions were excluded. TCD and Hb levels measured before HU initiation were defined as baseline (BL) levels. Cross-sectional correlations between TCD levels and Hb levels at 1 yr, 2 yrs and 4 yrs after HU initiation were assessed using Spearman correlation test. Among patients with conditional TCD level at BL, change in TCD levels at the end of 1 yr and 2 yrs after HU initiation were first summarized by change in Hb levels from BL (>0 g/dl, ≥0.5 g/dl, ≥1 g/dl, and ≥2 g/dl). A mixed- model repeated measures (MMRM) using longitudinal panel data were employed next to estimate the impact of Hb levels on TCD velocity, controlling for participants' demographic and clinical characteristics.


A total of 202 children (female: 46.5%, mean age at BL TCD: 7.53 yrs) were analyzed. At BL, 33 patients (16.3%) had conditional TCD level, 162 patients (80.2%) had normal TCD level. Mean (SD) BL Hb level was 8.4 g/dl (0.97 g/dl). In cross-sectional analysis, Hb was negatively associated with corresponding TCD levels at 1 yr, 2 yrs and 4 yrs post HU (Spearman correlation coefficients: -0.20, -0.64 and -0.38, respectively, all p-values <0.05).

The rates of converting from conditional to normal or abnormal TCD levels was assessed for the 33 children with BL conditional TCD levels. After 1 yr of HU therapy, 87% (n=21) of 24 children with conditional TCD whose Hb increased by ≥0.5 g/dL normalized their TCD level, and this number increased to 100% (n=4) when Hb increased by ≥2 g/dL. The same analysis was repeated after 2 yrs of HU initiation and yielded similar results: increases in ≥0.5 g/dL and ≥2 g/dL were associated with 88% and 100% of conversion to normal, respectively. No patients with a conditional TCD level at BL converted to abnormal TCD after 1 and 2 yrs of HU initiation. In the MMRM models, Hb was negatively associated with TCD levels: a 1 g/dL increase in Hb was associated with a 14 cm/sec reduction in TCD level (p<0.0001). After controlling for other patient characteristics (age, sex, BL Hb & TCD, time since HU initiation, and hemolysis markers), the impact of Hb on TCD levels was still significant.


In children with conditional TCD levels and elevated stroke risk prior to initiating hydroxyurea, the therapeutic rise in hemoglobin was significantly associated with a reduction in TCD levels. Importantly, the rise in hemoglobin was associated with a high likelihood of normalization of the TCD level when children had conditional TCD levels, which likely conveys a reduction in risk of stroke.


Estepp:Eli Lilly and Co: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Esperion: Consultancy; Forma Therapeutics: Research Funding. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Kang:MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Hankins:ASPHO: Honoraria; NHLBI: Honoraria; NHLBI: Research Funding; Bluebird Bio: Consultancy; Novartis: Research Funding; LYNKS Foundation: Research Funding; National Committee for Quality Assurance: Consultancy; Global Blood Therapeutics: Research Funding. Wang:Agios Pharmaceuticals: Consultancy; Novartis: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.